Novel mch receptor antagonists

ABSTRACT

The present invention relates to a melanin concentrating hormone antagonist compound of Formula I: (I) wherein Ar 1 , Ar 2 , Ar 3 , L 1 , L 2  and Q areas defined, or a pharmaceutically acceptable salt, solvate, enantiomer or mixture of diastereomers thereof useful in the treatment, prevention or amelioration of symptoms associated with obesity and Related Diseases.

FIELD OF THE INVENTION

The present invention is in the field of medicine, particularly in thetreatment of obesity and diseases caused by or exacerbated by obesity.More specifically, the present invention relates to antagonists ofmelanin concentrating hormone useful in the prevention and/or treatmentof obesity and related diseases.

BACKGROUND OF THE INVENTION

The affluence of the 90's along with the exponential increase in foodproduction particularly in Western and Asian economies has resulted infeeding patterns that lead to obesity. Obesity is defined as beingexcessively overweight. Excessive weight is generally characterized byexcessive body fat, because unused energy is stored in the adiposetissues as fat.

Obesity has associated with it, economic and social costs. Obese people,an increasing proportion of most western societies, are regarded ashaving out of control feeding habits often associated with lowself-esteem. Moreover, obese persons are more likely to have medicalproblems associated with or exacerbated by the excess body weight.Examples of medical conditions caused, exacerbated or triggered byexcessive weight include bone fractures, pains in the knee joints,arthritis, increased risk of hypertension, artherosclerosis, stroke,diabetes, etc.

Melanin concentrating hormone (MCH) is a 19 amino acid neuropeptideproduced in the lateral hypothalamic area and zona incerta, althoughMCH-expressing neurons project to numerous regions of the brain. MCH isprocessed from a larger pre-prohormone that also includes a secondpeptide, NEI, and possibly a third, NGE (Nahon, Crit Rev inNeurobiology, 8:221-262, 1994). MCH mediates its effects through atleast two G protein-coupled receptors, MCHR1 and MCHR2 (Saito et al.Nature 400: 265-269, 1999; Hill et al., J Biol Chem 276: 20125-20129,2001). Both receptors are expressed in regions of the brain consistentwith MCH neuronal projection and known MCH physiologic function (Hervieuet al., Eur J Neuroscience 12: 1194-1216, 2000; Hill et al., J Biol Chem276: 20125-20129, 2001; Sailer et al., Proc Nat Acad Sci 98: 7564-7569,2001).

Extensive evidence exists to support the orexigenic activity of MCH. MCHmRNA is elevated in rodent models of obesity and in the fasted state (Quet al., Nature 380: 243-247, 1996). Intracerebroventricularlyadministered MCH increases feeding and blocks the anorexic effect ofα-melanocyte stimulating hormone (Ludwig et al., Am J Physiol 274:E627-E633, 1998). MCH knock-out mice (MCH^(−/−) mice) are lean,hypophagic and hypometabolic (Shimada et al., Nature 396: 670-674,1998), while MCH over-expressing transgenic mice are obese and insulinresistant (Ludwig et al., J Clin Invest 107: 379-386, 2001). MCHR1^(−/−)mice have recently been reported to be lean and hypermetabolic,indicating that the R1 isoform mediates at least some of the metaboliceffects of MCH (Marsh et al., Proc Nat Acad Sci 99:3240-3245, 2002; Chenet al., Endocrinology, 2002, in press).

In addition to its effects on feeding, MCH has been implicated inregulation of the hypothalamic-pituitary-adrenal axis through modulationof CRF and ACTH release (Bluet-Pajot et al., J Neuroendocrinol 7:297-303, 1995). MCH may also play a role in the modulation ofreproductive function (Murray et al., J Neuroendocrinol 12: 217-223,2000) and memory (Monzon et al., Peptides 20: 1517-1519, 1999).

The current preferred treatment for obesity as well as Type IInon-insulin dependent diabetes is diet and exercise with a view towardweight reduction and improved insulin sensitivity for diabetics. Patientcompliance, however, is usually poor. The problem is compounded by thefact that there are currently only two medications approved for thetreatment of obesity (sibutramine, or Meridia™ and orlistat, orXenical™.

PCT application number WO 01/21577 (JP00/06375) filed Sep. 19, 2000,discloses compounds reportedly useful as antagonists of the MCHreceptor. In particular the WO 01/21577 application claims a compound offormula A

wherein:

Ar¹ is a cyclic group that may have substituents;

X is a spacer having a main chain of 1 to 6 atoms;

Y is a bond or a spacer having a main chain of 1 to 6 atoms;

Ar is a monocyclic aromatic ring which may be condensed with a 4 to 8membered non-aromatic ring, and may have further substituents;

R¹ and R² are independently hydrogen atom or a hydrocarbon group whichmay have substituents;

R¹ and R² together with the adjacent nitrogen atom may form anitrogen-containing hetereo ring which may have Substituents; R² mayform a spiro ring together with Ar; or R², together with the adjacentnitrogen atom and Y, may form a nitrogen-containing hetero ring whichmay have substituents; or salts thereof.

PCT application number WO 01/82925 also discloses compounds reportedlyusefull as antagonists of the MCH receptor. In particular the WO01/82925 application claims a compound of formula B

wherein:

Ar¹ is an optionally substituted cyclic group;

X and Y are independently a spacer having a C₁₋₆ main chain;

Ar is an optionally substituted fused polycyclic aromatic ring;

R¹ and R² are independently hydrogen atom or an optionally substitutedhydrocarbon group; or alternatively R¹ and R² together with the nitrogenatom adjacent thereto may form a nitrogenous heterocycle, or R² togetherwith the nitrogen atom adjacent thereto and Y may form an optionallysubstituted nitrogenous heterocycle, or R² together with the nitrogenatom adjacent thereto, Y, and Ar may form a fused ring.

PCT application number WO 01/87834 also discloses compounds reportedly25 useful as antagonists of the MCH receptor. In particular the WO01/87834 application claims a compound of formula C.

wherein;

R represents hydrogen, halogen, or an optionally substituted cyclicgroup; X represents a bond or a spacer in which the main chain has oneto ten atoms; Y represents a spacer in which the main chain has one tosix atoms; ring A represents a benzene ring which may have othersubstituents; ring B represents a five- to nine-membered nitrogenousnonaromatic heterocycle which may have other substituents; and R¹ and R²are the same or different and each represents hydrogen, an optionallysubstituted hydrocarbon group, or an optionally substituted heterocyclicgroup, or R¹ and R² may form an optionally substituted nitrogenousheterocycle in cooperation with the adjacent nitrogen atom and R² mayform an optionally substituted nitrogenous heterocycle in cooperationwith the adjacent nitrogen atom and Y.

Japanese patent application number JP2001-226269A also disclosescompounds reportedly useful as antagonists of the MCH receptor. Inparticular the JP2001-226269A application claims a compound of formulaD.

wherein:

Ar is a substituted group-contg. arom. ring, X₁ is a substitutedgroup-contg. divalent main chain of 1-5 atoms, X₂, X₃ and X₄ are linkingarms, and R2 is a basic substituting group, and its salts.

PCT application number WO 01/21169 also discloses compounds reportedlyuseful as antagonists of the MCH receptor. In particular the 01/21169application claims a compound of formula E.

Wherein:

Ar₁ and Ar₂ are each an optionally substituted aromatic group; P and Qare each a divalent aliphatic hydrocarbon group which may containethereal oxygen or sulfur in the carbon chain and may be substituted; R1and R3 are each (i) hydrogen, (ii) acyl, or (iii) optionally substitutedhydrocarbyl; R2 and R4 are each (i) hydrogen, (ii) optionallysubstituted alkyl, or (iii) optionally substituted alkylcarbonyl;alternatively R1 and R2 or R3 and R4 together with the nitrogen atomadjacent thereto may form a monocyclic or fused nitrogenous heterocyclicgroup; and j is 0 or 1, salts of the same, or prodrugs thereof.

PCT application number WO 02/04433 also discloses compounds reportedlyuseful as antagonists of the MCH receptor. In particular the 02/04433application claims a compound of formula F.

Wherein:

Q=(E)- or (Z)-CR10:CR11, C.triplebond.C, Formula G (whereinA=(un)substituted alkylene); R1-R8=H, halo, CN, etc.; R9-R19=H, allyl;W═N, CRa (Ra═H, OH, alkoxy, etc.); X=halo, CN, NO2, etc.; Y═O, S, SO,SO2; Z allyl, mono, di or trifluoromethyl, etc.

PCT application number WO 02/06245 also discloses compounds reportedlyuseful as antagonists of the MCH receptor. In particular the 02/06245application claims compounds of formula H, I, J, K, L, and M.

PCT application number WO 02/057233 also discloses compounds reportedlyuseful as antagonists of the MCH receptor. In particular the 02/057233application claims a compound of formula N

Wherein:

Ar₁=(un)substituted (hetero)aryl; Ar₂=(un)substituted (hetero)aryl,aralkyl; or Ar₁ and Ar₂ together form (un)substituted fluorene,fluorenone with the proviso that Ar₃ must be arylene; A₃=(un)substituted(hetero)arylene; X═O, S, N(CN); Y=a single bond, alkylene; R1=thiazole,(hetero)aryl, etc.; R2=H, alkyl].

PCT application number WO 02/51809 also discloses compounds reportedlyuseful as antagonists of the MCH receptor. In particular the 02/51809application claims a compound of formula O

Wherein:

W═R1-CR3R12NR4C(O), R11C(O)NR4; X═CHR8, C(O), C(═NOR9), when the doublebond is present CR8=; Y═CH, C(OH), C(alkoxy) or when the double bond ispresent C; R1=R5-cycloalkyl, R5-(hetero)aryl, R5-heterocycloalkyl;R2=R6-(hetero)aryl; n=1-3; R3=alkyl, (hetero)aryl; R4=H, alkyl; R5=H,alkyl, halo, OH, alkoxy, CF3, alkoxycarbonyl, SO2NHR4, C(O)NHR4,NR4C(O)NHR4, NR4C(O)R4, NR4SO2R4, etc.; R6=H, alkyl, halo, OH, SH,S(alkyl), CN, alkoxy, alkylcarboxy, CF3, NO2, NH2, alkylamino, Ph,alkoxycarbonyl, R7-phenoxy, etc.; R7=H, alkyl, halo, OH, alkoxy, CF3;R8=H, alkyl,alkoxyalkyl; R9=H, alkyl, arylalkyl; R10=H, alkyl, aryl;R11=cyclopropylphenyl or when R2=R6-heteroaryl or R10 is not H, R11 canalso be R5-phenyl-alkyl; m=1-5; R12=H, alkyl; R13=H, alkyl, halo, OH,alkoxy, CF3, OCF3, NO2, C(O)CH3; R14=H, alkyl, halo, OH, alkoxy, CF3.

PCT application number WO 02/10146 also discloses compounds reportedlyuseful as antagonists of the MCH receptor. In particular the 02/10146application claims a compound of formula P

Wherein:

A=H, C1-6alkyl optionally substituted by hydroxyl, C1-6alkoxy,C1-6alkenyl, C1-6 acyl, halogeno, OH, CN, CF3; R3=H, CH3, CH3CH2;R4=arom carbocycle, heterocycle; Z=O, S, NH, CH2, single bond, at the 3or 4 position of R4 relative to the carbonyl group; R5=arom. carbocycle,heterocycle; Q=XYNR1R2; X═O, S; Y═C2-4 alkylene, C5-6 cycloalkylene; R1,R2 independently=C1-6 alkyl, phenyl-C1-6 alkyl; R1R2=5-, 6-, 7-memberedring optionally contg. one or more heteroatom selected from O, S, N;etc.

PCT application number WO 02/76947 also discloses compounds reportedlyuseful as antagonists of the MCH receptor. In particular the 02/76947application claims a compound of formula Q

Current treatments targeted at obesity have side effects. Examples ofsuch treatments include phen-fen®, and various over-the-counter appetitesuppressants. These agents have not been proven effective for allpatients and for sustainable periods of time.

Therefore, there is a need for new and/or improved therapeuticallyeffective agents useful as anatagonists of melanin concentrating hormoneto better control the dietary habits, minimize the preponderance ofobesity and treat, prevent and/or ameliorate the effects of obesityincluding for example diabetes.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt, solvate, enantiomer, mixture ofdiastereomers, or prodrug thereof; wherein

Ar¹ is a cyclic group optionally substituted with one to five groupsselected from C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, hydroxy, C₁-C₈alkoxy, C₁-C₈ alkylaryl, phenyl, aryl, C₃-C₈ cycloalkyl, C₁-C₈alkylcycloalkyl, cyano, —(CH₂)_(n)NR¹R², C₁-C₈ haloalkyl, halo,(CH₂)_(n)COR⁶, (CH₂)_(n) NR⁵SO₂R⁶, —(CH₂)_(n)C(O)NR¹R², and C₁-C₈alkylheterocyclic;

wherein the alkyl, alkenyl, cycloalkyl, phenyl, and aryl are eachoptionally substituted with one to three groups selected from hydroxy,C₁-C₈ alkoxyalkyl, C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, nitro, cyano,amino, carboxamido, and oxo;

L¹ is a bond or a linker having a main chain of 1 to 14 atoms orrepresented by the formula X₂—(CR³R⁴)_(m)—X₃ wherein R³ and R⁴ areindependently hydrogen, C₁-C₈ alkyl, C₂-C₈ alkylene, C₂-C₈ alkynyl,phenyl, aryl, C₁-C₈ alkylaryl, (CH₂)_(n)NR⁵SO₂R⁶, (CH₂)_(n)C(O)R⁶,(CH₂)_(n)CONR¹R² or (CH₂)_(n)C(O)OR⁶; wherein the alkyl, alkenyl,phenyl, and aryl groups are optionally substituted with one to fivesubstitutents independently selected from oxo, nitro, cyano, C₁-C₈alkyl, aryl, halo, hydroxy, C₁-C₈ alkoxy, C₁-C₈ halaoalkyl,(CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR¹R² and (CH₂)_(n)C(O)OR⁶;

X₂ is independently —O, —CH, —CHR⁶, —NR⁵, S, SO, or SO₂;

X₃ is independently —O, —CH, —CHR⁶, —NR⁵, S, SO, or SO₂;

Ar² is a 6-member monocyclic carbocyclic or heterocyclic group orpositional isomer thereof, having 0, 1, 2, or 3 heteroatomsindependently selected from nitrogen, oxygen and sulfur; and optionallysubstituted with one to three substitutents selected from C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, hydroxy, C₁-C₈ alkoxy, C₁-C₈ alkylaryl,phenyl, aryl, C₃-C₈ cycloalkyl, C₁-C₈ alkylcycloalkyl, cyano, C₁-C₈haloalkyl, halo, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)C(O)OR⁶, (CH₂)_(n)NR⁵SO₂R⁶,(CH₂)_(n)C(O)NR¹R², and C₁-C₈ alkylheterocyclic;

provided that the result of the substitution is a stable fragment orgroup;

Ar³ is a 6-member monocyclic aromatic or nonaromatic, carbocyclic orheterocyclic ring having 0, 1, 2, or 3 heteroatoms selected fromnitrogen, oxygen and sulfur and optionally 10 substituted with one tothree substitutents independently selected from halo, —NHR⁵, C₁-C₈haloalkyl, C₃-C₈ cycloalkyl, C₁-C₈ alkyl, hydroxy, alkoxy,(CH₂)_(n)C(O)R⁶, (CH₂)_(n)C(O)OR⁶, (CH₂)_(n)NR⁵SO₂R⁶,(CH₂)_(n)C(O)NR¹R², phenyl, C₁-C₈ alkylaryl, and aryl;

provided that Ar² and Ar³ or positional isomn ersz thereof are linked bya bond;

L² is a bond or a divalent linker having a chain length of between 1 and14 atoms in the main chain or represented by the formula:

X₄—(CR³R⁴)_(m)—X₅ wherein R³ and R⁴ are independently hydrogen, C₁-C₈alkyl, C₂-C₈ alkylene, C₂-C₈ alkynyl, phenyl, aryl, C₁-C₈ alkylaryl,(CH₂)_(n)NR⁵SO₂R⁶, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR¹R² or(CH₂)_(n)C(O)OR⁶; wherein the alkyl, alkenyl, phenyl, and aryl groupsare optionally substituted with one to five substitutents independentlyselected from oxo, nitro, cyano, C₁-C₈ alkyl, aryl, halo, hydroxy, C₁-C₈alkoxy, C₁-C₈ halaoalkyl, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR¹R² and(CH₂)_(n)C(O)OR⁶;

wherein X₄ is selected from the group consisting of —CH, CHR⁶, —O, —NR⁵,—NC(O)—, —NC(S), —C(O)NR⁵—, —NR⁶C(O)NR⁶, —NR⁶C(S)NR⁶, —NRSO₂R⁷, and—NR⁶C(NR⁵)NR⁶;

X₅ is selected from the group consisting of —CH₂, —CH, —OCH₂CH₂, —SO,—SO₂, —S, and —SCH₂; wherein the group X₄—(CR³R⁴)_(m)—X₅ impartsstability to the compound of formula (1) and may be a saturated orunsaturated chain or linker;

Q is a basic group or a group represented by —NR¹R²; wherein R¹ and R²are independently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₃-C₈ cycloalkane, C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl, —C(O)OC₁-C₈ alkyl,C₁-C₈ alkylcycloalkane, (CH₂)_(n)C(O)OR⁵, (CH₂)_(n)C(O)R⁵,(CH₂)_(n)C(O)NR¹R², and (CH₂)_(n)NSO₂R⁵; wherein each of the alkyl,alkenyl, aryl are each optionally substituted with one to five groupsindependently selected from C₁-C₈ alkyl, C₂-C₈ alkenyl, phenyl, andalkylaryl; and wherein R¹ and R² may combine together, and with thenitrogen atom to which they are attached or with 0, 1, or 2 atomsadjacent to the nitrogen atom to form a nitrogen containing heterocyclewhich may have substituents;

R⁵ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₅-C₈ alkylaryl,(CH₂)_(n)NSO₂C₁-C₈ alkyl, (CH₂)_(n)NSO₂phenyl, (CH₂)_(n)NSO₂aryl,—C(O)C₁-C₈ alkyl, or —C(O)OC₁-C₈ alkyl; and

R⁶ is a group independently selected from hydrogen, C₁-C₈ alkyl, phenyl,aryl, C₁-C₈ alkylaryl, and C₃-C₈ cycloalkyl;

wherein m is an integer from 0 to 4; and n is an integer from 0 to 3.

The present invention also relates to a pharmaceutical formulationcomprising, a compound of formula I.

In another embodiment, the pharmaceutical formulation of the presentinvention may be adapted for use in treating obesity and relateddiseases.

The present invention also relates to a method for treating obesity in apatient in need thereof, wherein such treatment comprises administeringan effective amount of a compound of formula I in association with apharmaceutically acceptable carrier, diluent or excipient.

The present invention also relates to a method of antagonizing thebinding of MCH to MCH receptors useful for the treatment of diseasescaused, or exercabated by melanin concentrating hormone.

The present invention is related to the use of a compound of formula Ifor the manufacture of a medicament for treating obesity and relateddiseases.

DETAILED DESCRIPTION

For the purposes of the present invention, as disclosed and claimedherein, the following terms are defined below.

The term “main chain” as used herein describes the number of atoms inthe shortest distance between two ends of a variable or radical andincludes the distance in number of atoms when traversing a straightchain, branched chain or atoms in a mono or bicyclic ring from one endof the variable or radical to the other. For example the compoundPh-OCH₂CH₂CH₂S—CH₂Ph, if it represents the groups Ar¹L₁Ar², has a chainlength of 6 for L₁.

The term “C₁-C₈ alkyl” represents a straight or branched hydrocarbonmoiety having from one to eight carbon atoms, including but not limitedto methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, cyclobutyl, pentyl, hexyl, and the like. The term “C₁-C₈ alkyl”refers more preferably to methyl, ethyl, n-propyl, isopropyl,cyclopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl and the like.Similarly, the term C₂-C₈ alkenyl refers to a straight or branchedhydrocarbon chain having from 1 to 3 double bonds including positional,regio and sterochemcial isomers.

The term “C₃-C₈ cycloalkyl” as used herein refers to a cyclichydrocarbon radical or group having from 3 to 8 carbon atoms and havingno double bonds. Examples of C₃-C₈ cycloalkyl groups include but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl.

The term “C₃-C₈ cycloalkenyl” as used herein referes to a cyclichydrocarbon radical or group having from 3 to 8 carbon atoms and havingfrom 1 to 3 double bonds. Specific examples of C₃₋₈ cycloalkenyl includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, tetrahydrothiophene, tetrahydrofuran.

The term “halo” means halogens including iodo, chloro, bromo and fluoro.

The term “C₁-C₄ haloalkyl” refers to a C₁-C₄ alkyl group substitutedwith one, two or three halogen atoms as possible and as appropriate.Examples of C₁-C₄ haloalkyl include but are not limited totrifluoromethyl, chloroethyl, and 2-chloropropyl. Similarly, a “C₁-C₈haloalkyl” group is a C₁-C₈ alkyl moiety substituted with up to six haloatoms, preferably one to three halo atoms.

A “C₁-C₈ alkoxy” group is a C₁-C₈ alkyl moiety connected through an oxylinkage. The term includes “optionally halogenated C₁-C₈ alkoxy” groupsincluding for example, C₁-C₈ alkoxy (e.g. methoxy, ethoxy, propoxy,butoxy, pentyloxy, etc.), which may have 1 to 5, preferably 1 to 3,halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.). Concreteexamples of alkoxy groups include methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy.

The term “cyclic” as used herein refers to substituted or unsubstitutedaromatic and non-aromatic ring structures containing hydrocarbon groups,and substituted or unsubstituted aromatic and non-aromatic heterocyclicgroups. Cyclic groups may also be monocyclic, bicyclic or polycyclicunless otherwise specified. Examples of aromatic groups include, forexample, benzene, thiophene, furan, pyrrole, imidazole, pyrazole,thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrimidine,pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole,1,2,4,-thiadiazole, 1,3,4-thiadiazole, pyrrolidine, imidazoline,imidazolidine, pyrazoline, pyrazolidine, tetrahydrothiazole,tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole,piperidine, tetrahydropyridine, dihydropyridine, piperazine, morpholine,thiomorpholine, tetrahydropyrinidine, tetrahydropyridazine,hexamethyleneimine, benzofuran, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, isoquinoline,quinoline, indole, quinoxaline, phenanthridine, phenothiazine,phenoxathlin, phenoxazine, naphthylidene, quinazoline, carbazole,b-carboline, acridine, phenazine, phthalimide, and thioxanthene each ofwhich may be optionally substituted.

The term alkylcycloalkyl” as used herein refers to an alkylgroup onwhich a cycloalkyl group is substituted. Exemplary of alkylcycloalkylgroups are methylcyclopropyl, methylcyclohexyl, methylcycloheptyl,ethylcyclopropyl, etc. The alkylcycloalkyl group may optionally besustituted independently with one to five groups selected from C₁-C₈alkyl, phenyl, aryl, halo, amino, alkysulfonyl, alkylsulfonamide,haloalkyl, carboxyalkyl, carboxamide, alkoxy, and perfluoroalkoxy.

The term “optionally substituted” as used herein and unless otherwisespecified, means an optional substitution of one to five, preferably oneto two groups independently selected from halo, hydroxy, oxo, cyano,nitro, phenyl, benzyl, triazolyl, tetrazolyl, 4,5-dihydrothiazolyl,halo, C₁-C₆ alkyl, C₁-C₄ haloalkyl, C₁-C₆ alkoxy, COR⁷, CONR⁷R⁷, CO₂R⁷,NR⁷R⁷, NR⁷COR⁷, NR⁷SO₂R, OCOR⁸, OCO₂R⁷, OCONR⁷R⁷, SR⁷, SOR⁸, SO₂R⁸ andSO₂(NR⁷R⁷), where R⁷ is independently at each occurrence H, C₁-C₆ alkylphenyl or benzyl and R⁸ is independently at each occurrence C₁-C₆ alkyl,phenyl or benzyl.

The term “heterocycle” or “heterocyclic” represents a stable, saturated,partially unsaturated, fully unsaturated or aromatic 4, 5, or 6 memberedring, said ring having from one to three heteroatoms that areindependently selected from the group consisting of sulfur, oxygen, andnitrogen. The heterocycle may be attached at any point which affords astable structure. Representative heterocycles include 1,3-dioxolane,4,5-dihydro-1H-imidazole, 4,5-dihydrooxazole, furan, imidazole,imidazolidine, isothiazole, isoxazole, morpholine, oxadiazole, oxazole,oxazolidinedione, oxazolidone, piperazine, piperidine, pyrazine,pyrazole, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolidine, tetrazole, thiadiazole, thiazole, thiophene and triazole.The heterocycle is further optionally substituted with one-to three,preferably one or two groups independently selected from halo, hydroxy,oxo, cyano, nitro, phenyl, benzyl, triazolyl, tetrazolyl,4,5-dihydrothiazolyl, C₁-C₆ alkyl, C₁-C₄ haloalkyl, C₁-C₆ alkoxy, COR⁷,CONR⁷R⁷, CO₂R⁷, NR⁷R⁷, NR⁷COR⁷, NR⁷SO₂R⁸, OCOR⁸, OCO₂R⁷, OCONR⁷R⁷, SR⁷,SOR⁸, SO₂R⁷ and SO₂(NR⁷R⁷), where R⁷ is independently at each occurrenceH, C₁-C₆ alkyl, phenyl or benzyl and R⁸ is independently at eachoccurrence C₁-C₆ alkyl, phenyl or benzyl.

The term “alkylheterodyclic” as used herein refers to an alkyl groupfurther substitued with a heterocyclic group. Examples ofalkylheterocycles include but are not limited to 2-methylimidazoline,N-methylmorpholinyl, N-methylpyrrolyl and 2-methylindolyl.

The term “basic radical” refers to an organic radical which is a protonacceptor. Illustrative basic radicals are amidino, guanidino, amino,piperidyl, pyridyl, etc.

The term “basic group” refers to an organic group containing one or morebasic radicals. A basic group may comprise only a basic radical.

Suitable basic radicals contain one or more nitrogen atoms and includeamino, imino, amidino, N-alkylamidines, N,N′-dialkylamidines,N-arylamidines, aminomethyleneamino, iminomethylamino, guanidino,aminoguanidino, alkylamino, dialkylamino, trialkylaniino,alkylideneamino, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl,purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, amide,thioamide, benzamidino, pteridinyl, 4H-carbazolyl, carbazolyl,beta-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, or anyof the preceding substituted with amino, imino, amidino,aminomethyleneamino, iminomethylamino, guanidino, alkylamino,dialkylamino, trialkylamino, tetrahydroisoquinoline, dihydroisoindole,alkylideneamino, groups, or a group represented by the formula NR¹R².

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction, that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

As used herein, the term “patient” includes human and non-human animalssuch as companion animals (dogs and cats and the like) and livestockanimals. Livestock animals are animals raised for food production.Ruminants or “cud-chewing” animals such as cows, bulls, heifers, steers,sheep, buffalo, bison, goats and antelopes are examples of livestock.Other examples of livestock include pigs and avians (poultry) such aschickens, ducks, turkeys and geese. Also included are exotic animalsused in food production such as alligators, water buffalo and ratites(e.g., emu, rheas or ostriches). The preferred patient of treatment is ahuman.

The terms “treating” and “treat”, as used herein, include theirgenerally accepted meanings, i.e., preventing, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, or reversing theprogression or severity of a pathological condition, or sequela thereof,described herein.

The terms “preventing”, “prevention of”, “prophylaxis”, “prophylactic”and “prevent” are used herein interchangeably and refer to reducing thelikelihood that the recipient of a compound of formula I will incur ordevelop any of the pathological conditions, or sequela thereof,described herein.

As used herein, the term “effective amount” means an amount of acompound of formula I that is sufficient for treating a condition, ordetrimental effects thereof, herein described, or an amount of acompound of formula I that is sufficient for antagonizing the MCHR1receptor to achieve the objectives of the invention.

The term “pharmaceutically acceptable” is used herein as an adjectiveand means substantially non-deleterious to the recipient patient.

The term “formulation”, as in pharmaceutical formulation, is intended toencompass a product comprising the active ingredient(s) (compound(s) offormula I), and the inert ingredient(s) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical formulations of the presentinvention encompass any composition made by admixing a compound of thepresent invention and a pharmaceutical carrier, or a compound of theformula I and a pharmaceutically acceptable co-antagonist of MCHR1useful for the treatment and/or prevention of obesity or a relateddisease where antagonism of a MCH receptor may be beneficial.

The terms “diseases related to obesity” or “related diseases” as usedherein refer to such symptoms, diseases or conditions caused by,exacerbated by, induced by or adjunct to the condition of being obese.Such diseases, conditions and/or symptoms include but are not limited toeating disorders (bulima, anorexia nervosa, etc.), diabetes, diabeticcomplications, diabetic retinopathy, sexual/reproductive disorders (suchas ercetile dysfunction, loss of libido), depression, anxiety, epilepticseizure, hypertension, cerebral hemorrhage, conjestive heart failure,sleeping disorders, atherosclerosis, rheumatoid arthritis, stroke,hyperlipidemia, hypertriglycemia, hyperglycemia, andhyperlipoproteinenamia.

The term “unit dosage form” refers to physically discrete units suitableas unitary dosages for human subjects and other non-human animals (asdescribed above), each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical carrier.

Because certain compounds of the invention contain an acidic moiety(e.g., carboxy), the compound of formula I may exist as a pharmaceuticalbase addition salt thereof. Such salts include those derived frominorganic bases such as ammonium and alkali and alkaline earth metalhydroxides, carbonates, bicarbonates, and the like, as well as saltsderived from basic organic amines such as aliphatic and aromatic amines,aliphatic diamines, hydroxy alkalines, and the like.

Because certain compounds of the invention contain a basic moiety (e.g.,amino), the compound of formula I may also exist as a pharmaceuticalacid addition salt. Such salts include the salicylate, sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, benzoate,chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, hippurate, β-hydroxybutyrate, glycolate, maleate,tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and like salts. Preferred acidaddition salts include the hydrochloride and glycolate salts. Acidaddition salts are typically formed by reacting an equivalent amount ofacid (based on moles of available basic i.e free pairs of electrons onnitrogen atoms, or a slight excess thereof) with the free base compoundof the invention. The addition salt product is often isolated as thecrystallization product. The crystallization may be spontaneous or maybe facilitated by cooling and or seeding. Other methods of isolating theacid addition salts are known to one of skill in the art.

PREFERRED COMPOUNDS OF THE INVENTION

Certain compounds of the invention are particularly preferred. Thefollowing listing sets out several groups of preferred variables and/orcompounds. It will be understood that each of the listings may becombined with other listings to create additional groups of preferredcompounds.

Preferred Ar¹

Preferred Ar¹ groups are cyclic groups selected from cycloalkyl andcycloalkene groups such as the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl; and groups selected from tetrahydrothiophene,tetrahydrofuran, pyrrolidine, imidazoline, imidazolidine, indole,isoindolylyl, pyrazoline, pyrazolidine, tetrahydrothiazole,tetrahydroisothiazole, tetrahydrooxazole, phenyl, tetrahydroisoxazole,piperidine, tetrahydropyridine, benzothiophene, benzofuran, naphthyl,dihydropyridine, piperazine, morpholine, thiomorpholine,tetrahydropyrimidine, tetrahydropyridazine, hexamethyleneimine, eachoptionally substituted with C₁-C₆ alkyl, C₁-C₆ cycloalkyl, C₁-C₆haloalkyl, hydroxy, alkoxyalkyl, cyano, halo, phenyl, aryl, carboxamide,and C₁-C₆ carboxyalkyl. More preferred Ar¹ groups include cycloalkyl,cycloalkenyl, phenyl, benzothiophene, benzofuran and naphthyl.

Preferred L¹ Groups

Preferred L¹ groups are selected from the group consisting of —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —SCH₂—, —OCH₂—, —CH₂SCH₂—, —CH₂OCH₂—,—OCH₂CH₂SCH₂—, —OCH₂CH₂OCH₂—, —O(CH₂)₃SCH₂—, —OCH(Et)CH₂CH₂SCH₂,—OCH(iPr)CH₂CH₂SCH₂, —OCH(CH₃)CH₂CH₂SCH₂,—O(CH₂)₃SCH(CH₃)—,—O(CH₂)₂SCH(CF₃)—, —OCH₂CH(NO₂)SCH₂—, —OCH(CN)CH₂SCH₂,—OCH₂CH(NH₂)SCH₂—, —CH₂O(CH₂)₃CH₂O—, and —CH₂O(CH₂)₂CH₃O—.

Also preferred is an L₁ group having the formula X₂—(CR³R⁴)_(m)—X₃wherein a preferred X₂ group is selected from O, S, and —NR⁶, wherein R⁶is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₃-C₈ cycloalkyl, phenyl, benzyl, C₁-C₈ alkylamine, and aryl.

Preferred X₃ Groups

Also preferred is an L¹ group wherein, when L¹ is X₂—(CR³R⁴)_(m)—X₃; X₃is a group selected from —OCH₂, —SCH₂, —NR⁶C(O)CH₂, —NHCH₂, wherein R⁶is selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₃-C₈ cycloalkyl, phenyl, benzyl, and aryl. More preferred isan X₃ group selected from —OCH₂, and —SCH₂.

Also preferred is a compound of formula I wherein L¹ isX₂—(CR³R⁴)_(m)—X₃, and wherein the chain between X₂ and X₃ i.e.,—(CR³R⁴)_(m)— is an alkyl chain of 3 to 8 carbon atoms, or an alkenylchain of 3 to 8 carbon atoms and optionally having an alkyl, phenyl,amino, or cycloalkyl group as a side chain.

Preferred Ar² Groups

A preferred Ar² group is a 6-member monocyclic carbocyclic orheterocyclic group having 0, 1 or 2 heteroatoms selected from oxygen,sulfur, and nitrogen. More preferred is a group selected frompyridazinyl, pyrimidinyl, pyran, piperidinyl, phenyl, cyclohexyl,pyridinyl and piperazinyl. Most preferred Ar² is the group phenyl,preferably attached in a 1,2. or 1,3 relationship to the Ar³ group.

Preferred Ar³ Groups

A preferred Ar³ group is a 6-member carbocyclic or heterocyclic grouphaving 0, 1, 2, or 3 heteroatoms independently selected from oxygen,sulfur, and nitrogen and optionally substituted with one to two groups.More preferred is a cyclic group selected from phenyl, pyran,piperidine, pyridine, pyridazine, and piperazine. Most preferred Ar³ isphenyl.

Preferred L² Groups

Certain preferred L² groups are selected from the group consisting of—OCH₂CH₂—, —O(CH₂)₃—, —CH₂, —CH₂CH₂, —CH₂CH₂CH₂, —CH═CH, —CH₂CH₂CH═CH—and X₄—(CR³R⁴)_(m)—X₅.

Preferred X₄ Groups

Preferred X₄ groups include divalent groups, radicals, or fragments ofthe formula —C(O)NR⁶ wherein R⁶ is selected from the group consisting ofhydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, phenyl, benzyl,C₁-C₈ alkylamine, and aryl.

Also preferred is an X₄ group selected from O, S, —NR⁶C(O)NR⁶, —C(S)NR⁶,NR⁶C(S)NR⁶, NR⁶C(NR⁶)NR⁶, —NR⁶SO₂—, wherein R⁶ is independently selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₈cycloalkyl, phenyl, benzyl, C₁-C₈ alkylamine, and aryl.

Preferred X₅ Groups

Preferred is an X₅ group selected from —OCH₂, —SCH₂, O, —NR⁶C(O),—NR⁶C(S), —C(O)NR⁶, —C(S)NR6, NR⁶C(S)NR⁶, NC(NR⁶)N, NR⁶C(O)NR⁶, —NR⁶SO₂wherein R⁶ is independently selected from the group consisting ofhydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, phenyl, benzyl,C₁-C₈ alkylamine, and aryl. More preferred is an X₅ group selected from—OCH₂, SCH₂ and O.

Also preferred is a compound of formula I wherein the chain between X₄and X₅ is preferably an alkyl chain of 2 to 8 carbon atoms, or analkenyl chain of 2 to 8 carbon atoms and optionally contains an allyl,phenyl, or cycloalkyl group as a side chain.

Preferred Q Groups:

The substituent Q of formula I is a basic group. A basic group is anorganic group containing one or more basic radicals. Preferred Q groupsare those represented by the formula —NR¹R².

Preferred R¹ and R² Groups

Preferred R¹ and R² groups are independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl,C₃-C₈ alkylcycloalkyl, phenyl, benzyl, COR⁹, SO₂R⁹, and (CH₂)_(n)SO₂R⁶.

Also preferred are R¹ and R² groups which combine with each other, andthe nitrogen atom to which they are attached to form a heterocycleselected from morpholino, thiomorpholino, pyrrole, 2H-pyrrole,2-pyrroline, pyrrolidine, oxazole, thiazole, imidazoline, imidazolidine,pyrazole, pyrazoline, piperazinyl, piperadinyl, pyrazinyl, pyrimidineeach optionally substituted with a C₁-C₈ alkyl group.

Also preferred is a compound of the invention having R¹ and R² groupswherein the R¹ and R² groups combine with the nitrogen atom to whichthey are attached and with a carbon atom one or two atoms removed fromthe nitrogen atom to form a cycle such as for example, azepine,diazepine, pyridine, piperidine, indolyl, N-methylpyrrolidinyl,pyrrolidinyl, morpholino, piperidinyl, and the like.

Most preferred are R₁ and R₂ which singly or in combination with eachother and/or the nitrogen atom to which they are attached form thegroups independently selected from methyl, ethyl, propyl, isopropyl,isobutyl, cyclopentyl, cyclohexyl, N-morpholino, azepane, diazepine,pyridine, pyrrolidine, piperidine, N-methylpiperidine, andN-methylpiperazine.

Preferred R³ and R⁴ Groups:

Preferred R³ and R⁴ are independently selected from hydrogen, C₁-C₈alkyl, C₂-C₈ alkylene, C₂-C₈ alkynyl, phenyl, aryl, C₁-C₈ alkylaryl,(CH₂)_(n)NR⁵SO₂R⁶, (CH₂)_(n)C(O)R⁶ (CH₂)_(n)CONR¹R² and(CH₂)_(n)C(O)OR⁶; wherein the alkyl, alkenyl, phenyl, and aryl groupsare optionally substituted with one to three substitutents independentlyselected from oxo, nitro, cyano, C₁-C₈ alkyl, aryl, halo, hydroxy, C₁-C₈alkoxy, C₁-C₈ halaoalkyl, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR¹R² and(CH₂)_(n)C(O)OR⁶. Most preferred R³ and R⁴ substituents areindependently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈ alkylene, C₂-C₈alkynyl, phenyl, and benzyl; and wherein n is 0, or 1, and wherein R⁵ ishydrogen, C₁-C₈ alkyl, phenyl or benzyl; and wherein R⁶ is hydrogen,C₁-C₈ alkyl, phenyl or benzyl.

Preferred R⁵ Groups

A preferred R⁵ group is a group independently selected from hydrogen,C₁-C₈ alkyl, C₁-C₈ alkoxy, C₂-C₈ alkenyl, C₅-C₈ alkylaryl,(CH₂)_(n)NSO₂C₁-C₈ alkyl, (CH₂)_(n)NSO₂phenyl, (CH₂)_(n)NSO₂aryl,—C(O)C₁-C₈ alkyl, and —C(O)OC₁-C₈ alkyl.

Preferred R⁶ Groups

A preferred R⁶ group is a group independently selected from hydrogen,C₁-C₈ alkyl, phenyl, aryl, alkylaryl, and C₃-C₈ cycloalkyl.

A particularly preferred compound of the present invention is a compoundselected from the group consisting of:

-   4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic    acid(3-dimethylamino-propyl)-amide oxalate-   4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic    acid(2-dimethylamino-ethyl)-amide oxalate,-   4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic    acid(4-dimethylamino-butyl)-amide oxalate,-   4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic    acid(2-dimethylamino-ethyl)-amide oxalate,-   4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic    acid(3-dimethylamino-propyl)-amide hydrochloride,-   4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic    acid(4-dimethylamino-butyl)-amide oxalate,-   4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic    acid(2-dimethylamino-ethyl)-amide oxalate,-   4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic    acid(3-dimethylamino-propyl)-amide,-   4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic    acid(4-dimethylamino-butyl)-amide oxalate,-   3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic    acid(2-dimethylamino-ethyl)-amide hydrochloride,-   3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic    acid(3-dimethylamino-propyl)-amide,-   3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-caxboxylic    acid(4-dimethylamino-butyl)-amide,-   3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic    acid(3-dimethylamino-propyl)-amide oxalate,-   3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic    acid(2-dimethylamino-ethyl)-amide,-   3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic    acid(3-dimethylamino-propyl)-amide oxalate,-   3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic    acid(4-dimethylamino-butyl)-amide oxalate,-   2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic    acid(2-dimethylamino-ethyl)-amide oxalate,-   2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic    acid(3-dimethylamino-propyl)-amide,-   2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic    acid(4-dimethylamino-butyl)-amide oxalate,-   2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic    acid(2-dimethylamino-ethyl)-amide oxalate,-   2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic    acid(3-dimethylamino-propyl)-amide oxalate,-   2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic    acid(4-dimethylamino-butyl)-amide oxalate,-   2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic    acid(2-dimethylamino-ethyl)-amide,-   2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic    acid(3-dimethylamino-propyl)-amide,-   2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic    acid(4-dimethylamino-butyl)-amide,-   or a pharmaceutically acceptable salt, enatiomer, solvate or prodrug    thereof.

PREPARING COMPOUNDS OF THE INVENTION

Compounds of formula I may be prepared as described in the followingSchemes and Examples.

Precursors to the compounds of the invention are prepared by methodsknown to one of skill in the art. The compounds employed as initialstarting materials in the synthesis of compounds of the invention arewell known and, to the extent not commercially available, are readilysynthesized by standard procedures commonly employed by those ofordinary skill in the art.

More particularly, the compounds of the invention are produced inaccordance with the General Methods 1 through 5 that are described indetail below, or analogous methods thereto. These reactions are oftencarried out in accordance with known methods, or analogous methodsthereto. Examples of such known methods include the methods described ingeneral reference texts such as Organic Functional Group Preparations,2^(nd) Edition, 1989; Comprehensive Organic Transformations, VCHPublishers Inc, 1989; Compendium of Organic Synthetic Methods, Volumes1-10, 1974-2002, Wiley Interscience; March's Advanced Organic Chemistry,Reactions Mechanisms, and Structure, 5^(th) Edition, Michael B. Smithand Jerry March, Wiley Interscience, 2001, Advanced Organic Chemistry,4^(th) Edition, Part B, Reactions and Synthesis, Francis A. Carey andRichard J. Sundberg, Kluwer Academic/Plenum Publishers, 2000, etc., andreferences cited therein.

General Method 1: Coupling of the Basic Group

The compounds of Formula 3 can be prepared by the General Method 1,described in General Scheme 1, via coupling of a compound of Formula 2containing a basic group with a group of Formula 1, where during thecourse of the coupling reaction the coupling groups are retained or lostto form the linker L₂ between the basic group and the phenyl ring. Ar¹,L¹, Ar², L², and basic group are defined as above. In the schemes thatfollow Ar³ of formula I has been depicted as a phenyl group forconvenience only and is not intended to be limiting. Also, L_(a) isdefined as a group that when the coupling process occurs results in theformation of the linker L² defined above. Furthermore, in the schemesthat follow, the group L¹ is depicted by the combination of group orgroups interspacing or linking the groups Ar¹ and Ar². Similarly, thegroup L² is depicted by the combination of group or groups interspacingor linking the groups Ar³ and the basic group. The basic group of thecompounds of the following schemes in general mean the group —N(R¹R²)unless otherwise indicated. Examples of the General Method 1 are aDisplacement Process (Scheme 1a) and a Reductive Amination Process(Scheme 1b).

As outlined in Scheme 1a below, the coupling process of General Method 1may consist of a displacement process whereby nucleophilic displacementof a leaving group, such as, but not limited to halogen, triflate,tosylate, brosylate, mesylate, nosylate, nonaflate, tresylate, and thelike, of Formula 4, by a nucleophilic basic group of Formula 5 affordsthe compounds of the invention. A leaving group is defined in one ormore of the general reference texts described previously.

One to five equivalents of the nucleophilic basic group of Formula 5 andone to five equivalents of the reactive derivative of Formula 4 may bereacted in the presence, or absence, of an inert solvent.

If necessary, the reaction may be carried out in the presence of acatalytic quantity to about five equivalents of a non-interfering base.A non-interfering base is a base suitable for the intended reaction byvirtue of the base not deleteriously affecting the reaction. One to twoequivalents of base is normally preferable. The reaction is normallycarried out between 0° C. and 120° C. Reaction time is normally 4 to 24hours.

Nucleophilic basic groups would include, but would not be limited toammonia, primary and secondary amines, guanidines, and the like.Specific nucleophilic basic groups include ammonia, methylamine,dimethylamine, diethylamine, diisopropylamine, pyrrolidine, piperidine,morpholine, azetidine, thiomorpholine, piperazine, imidazole, and thelike. Among the above nucleophilic basic groups dimethylamine,pyrrolidine, and piperidine are preferable.

If necessary, the reaction can be carried out with nucleophilic basicgroup synthon, i.e., a group that could readily be converted to a basicgroup by methods known to one skilled in the art. Nucleophilic basicgroup synthons would include, but would not be limited to, azide,phthalimide, protected amines, hexamethylenetetramine, cyanamide,cyanide anion, and the like. Following the displacement reaction, thesegroups would then be unmasked under standard conditions to afford thebasic group. For example, displacement with potassium phthalimidefollowed by removal of the phthalimide group to afford the primary amineas in the Gabriel synthesis (see, March's Advanced Organic Chemistry,Reactions Mechanisms, and Structure, 5^(th) Edition, Michael B. Smithand Jerry March, Wiley Interscience, 2001, Chapter 10, and referencescited therein). Application of the synthon equivalent to the basic groupapplies to the processes described in all of the General Methods 1through 5. Examples of “inert solvent” include amide solvents(preferably DMF or DMAC), sulfoxide solvents (preferably DMSO), sulfonesolvents (preferably sulfolane or dimethylsulfone), nitrile solvents(preferably acetonitrile), halogenated hydrocarbon solvents (preferablydichloromethane), aromatic solvents (preferably toluene or benzene),ether solvents (preferably diethylether or THF), ketone solvents(preferably acetone), ester solvents (preferably ethyl acetate), alcoholsolvent (preferably MeOH or EtOH), etc. Two or more of the solvents canbe mixed in an appropriate ratio for use. Among the above solvents, DMFand DMSO are preferable.

Examples of “base” include, for instance, hydrides of alkali metals andalkaline earth metals (e.g., lithium hydride, sodium hydride, potassiumhydride, and the like), amides of alkali metals and alkaline earthmetals (e.g., sodium amide, lithium diisopropyl amide, lithiumhexamethyldisilazide, and the like), alkoxides (e.g. sodium methoxide,sodium ethoxide, potassium t-butoxide, and the like), inorganic bases,such as hydroxides of alkali metals or alkaline earth metals (e. g.,sodium hydroxide, lithium hydroxide, potassium hydroxide, and the like),carbonates and hydrogen carbonates of alkali metals or alkaline earthmetals (e. g., potassium carbonate, sodium bicarbonate, sodiumcarbonate, cesium carbonate, and the like), amine bases (such as,N-methylmorpholine, DBU, DBN, pyridine, 2,6-lutidine, triethylamine,diisopropylethylamine, and the like). Among the above bases, sodiumhydride, potassium carbonate, and cesium carbonate are preferable.

As outlined in Scheme 1b below, the coupling process can consist of aReductive Amination Process. A compound of Formula 6 is condensed withammonia, or a primary, or secondary amine under dehydration/reductionconditions. Scheme 1b is a process analogous to that described in forexample, Chem Pharm Bull 1999, 47 (8), 1154-1156; Synlett 1999, (11),1781-1783; and J Med Chem 1999, 42 (26), 5402-5414 and references citedtherein.

The carbonyl compound of Formula 6 is reacted with an amine of Formula 7in an inert solvent under conditions that form the iminium species ofFormula 8. The iminium species is reduced in-situ to form the compoundsof Formula 3. The reaction is normally done in the presence of adehydrating agent and a reducing agent. Amines of Formula 7 include, butare not be limited to ammonia, primary and secondary amines, and thelike. Specific amine groups include ammonia, methylamine, dimethylamine,diethylamine, diisopropylamine, pyrrolidine, piperidine, morpholine,azetidine, thiomorpholine, piperazine, imidazole, and the like. One tofive equivalents of the amine group of Formula 7 and one to fiveequivalents of the reactive derivative of Formula 6 are reacted in thepresence, or absence, of an inert solvent. The use of an excess ofdehydrating agent is normally preferable. The reaction is carried out inthe presence of one to hundred equivalents of a reducing agent. One tothree equivalents of reducing agent is preferable. The reaction isnormally carried out between 0° C. and 120° C. Reaction time is normally4 to 24 hours. For the above amination reaction, MeOH and EtOH arepreferable as inert solvents.

Examples of “dehydrating agents” include anhydrous molecular sievesbeads, anhydrous molecular sieve pellets, powdered anhydrous molecularsieves, anhydrous molecular sieves on supports (such as zeolite),anhydrous magnesium sulfate, anhydrous sodium sulfate, and the like.Among the above dehydrating agents, anhydrous molecular sieves pelletsand powdered anhydrous molecular sieves are preferable. Examples of“reducing agents” include hydrogen gas or hydrogen gas precursor and ahydrogenation catalyst. Other “reducing agents” include sodiumcyanoborohydride, sodium triacetoxyborohydride, sodium borohydride,sodium borohydride/Ti (Oi-Pr)4, borohydride-exchange resin, and thelike. Examples of “hydrogen gas precursors” include formic acid,1,4-cyclohexadiene, and the like. Examples of “hydrogenation catalyst”include 5-10% palladium on carbon, 1-10% platinum on carbon, rhodium,ruthenium, nickel and the like. The metal can be used as a finelydispersed solid or absorbed on a support, such as carbon or alumina.Among the above reducing agents, sodium cyanoborohydride and sodiumtriacetoxyborohydride are preferred.

Gentera Method 2: Coupling of the Linker Group

The compounds of Formula 3 can be prepared by the General Method 2,described in General Scheme 2, via reaction of the coupling group ofFormula 9 with a coupling group of Formula 10, Examples of the GeneralMethod 2 are an Ether/Thioether Alkylation Process (Scheme 2a), anAcylation/Sulfonylation Process (Scheme 2b), Urea/Thiourea/GuanidineCoupling Process (Scheme 2cl, 2c2, 2c3), an Organometallic Process(Scheme 2d), and a Wittig-type Coupling (Scheme 2e).

As outlined in Scheme 2a below, the coupling process of General Method 2can consist of a Ether/Thioether Alkylation Process. Nucleophilicdisplacement by an alcohol or thiol-containing compound of Formula 11(or Formula 11′) with a compound of Formula 12 (or Formula 12′)containing a leaving group affords the ether and thioether compounds ofFormula 13. Scheme 2a is a process analogous to that described in TheChemistry of the Ether Linkage; Patai, Wiley, 1967, 446, 460; and inMarch's Advanced Organic Chemistry, Reactions Mechanisms, and Structure,5^(th) Edition, Michael B. Smith and Jerry March, Wiley Interscience,2001, Chapter 10.

One to five equivalents of the alcohol or thiol of Formula 11 (orFormula 11′) and one to five equivalents of the reactive derivative ofFormula 12 (or Formula 12′) are reacted in the presence, or absence, ofan inert solven. If necessary, the reaction can be carried out in thepresence of a catalytic quantity to ten equivalents of a non-interferingbase. One to three equivalents of base is normally preferable. Thereaction is typically carried out between 0° C. and 120° C. Reactiontime is typically from about 4 to about 24 hours, but may be shorter orlonger depending on the particular substrate. Preferred bases for theabove reaction include sodium hydride, potassium carbonate and cesiumcarbonate.

If necessary, the reaction may be performed with basic group synthonincorporated as the basic group in Formula 12, i.e., a group that couldreadily be converted to a basic group by methods known to one skilled inthe art. Basic group synthons would include, but not be limited to,halogen, protected amine, nitrile, aldehyde, and the like. Following theether/thioether alkylation reaction, these groups would then be unmaskedor converted under standard conditions to afford the basic group. Forexample, alkylation with 1-iodo-4-chloro-butane would give a4-chlorobutane derivative of compound 11. The chloride could then beconverted by the Displacement Process, described above in Scheme 1a,into the basic group of a compound of Formula 13. Among the inertsolvents, DMF and DMSO are preferable.

As outlined in Scheme 2b below, the coupling process of General Method 2can consist of a Acylation/Sulfonylation Process. Acylation orsulfonylation of an alcohol or amine compound of Formula 14 with acarboxylic acid or sulfonic acid compound of Formula 15, affords theester, amide, sulfonic ester, or sulfonamide compounds of Formula 16.Alternatively, acylation or sulfonylation of an alcohol or aminecompound of Formula 18 with a carboxylic acid or sulfonic acid compoundof Formula 17 affords the ester, amide, sulfonic ester, or sulfonamidecompounds of Formula 19. If necessary, the reaction can be carried outwith a basic group synthon incorporated as the basic group in Formula 15or Formula 18, i.e., a group that could readily be converted to a basicgroup by methods known to one skilled in the art. Basic group synthonswould include, but not be limited to, halogen, protected amine, nitrile,aldehyde, and the like. Following the Acylation/Sulfonylation reaction,these groups would then be unmasked or converted under standardconditions to afford the basic group.

The carboxylic acid (or sulfonic acid) residue of compound 15 (orcompound 17) is activated for coupling as a “reactive acylating agent.”“Reactive acylating agents” are described in detail in Advanced OrganicChemistry, 4^(th) Edition, Part B, Reactions and Synthesis, Francis A.Carey and Richard J. Sundberg, Kluwer Academic/Plenum Publishers, 2000,Chapter 3, and references cited therein. The “reactive acylating agent”can be formed and isolated, then reacted with the compound of Formula 14(or 18), or formed in situ and reacted with the compound of Formula 14(or 18), to form the compound of Formula 16 (or 19). One to fiveequivalents of the “reactive acylating agent” of compound 15 (orcompound 17) and one to five equivalents of compound of Formula 14 (or18) are reacted in an inert solvent. If necessary the reaction maybecarried out in the presence of one to five equivalents of1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and/or a catalyticquantity to five equivalents of a base. The reaction is normally carriedout between 0° C. and 120° C. Reaction time is normally 4 to 48 hours.

Examples of “reactive acylating agent” of compound 15 (or compound 17)include acid halides (e.g., acid chloride, acid bromide, and the like),mixed acid anhydrides (e. g., acid anhydrides with C₁-C₆alkyl-carboxylic acid, C₆-C₁₀ aryl-carboxylic acid, and the like),activated esters (e. g., esters with phenol which may have substituents,1-hydroxybenzotriazole, N-hydroxysuccinimide,1-hydroxy-7-azabenzotriazole, and the like), thioesters (such as,2-pyridinethiol, 2-imidazolethiol, and the like), N-acylimidazoles(e.g., imidazole, and the like), etc.

A “reactive acylation agent” may also be formed reacting the carboxylicacid (or sulfonic acid) residue of compound 15 (or compound 17) with adehydration/condensation agent. Examples of a “dehydration/condensationagent” include dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),(2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and the like.Preferred solvents for the above reaction include acetonitrile, THF, anddichloromethane. Preferred bases for the above reaction includetriethylamine, pyridine, and dimethylaminopyridine.

As outlined in Scheme 2cl, Scheme 2c2, and Scheme 2c3 below, thecoupling process of General Method 2 can consist of aUrea/Thiourea/Guanidine/Carbamate-Type Coupling Process. The processesbut not the compounds described are analogous to that described in U.S.Pat. Nos. 5,849,769 and 5,593,993, and references cited therein.

One to five equivalents of the isocyanate, isothiocyanate, orcarbodiimide of Formula 20 and one to five equivalents of compound ofFormula 21 are reacted in an inert solvent. The reaction is typicallycarried out between 0° C. and 150° C. Preferred reaction time is between4 to 48 hours. Preferred solvents for the above reaction includeacetonitrile, DMF, DMSO, THF, and dichloromethane.

If necessary, the reaction can be carried out with a basic group synthonincorporated as the basic group wherein a synthon is as describedealier. Following the Urea/Thiourea/Guanidine/Carbamate-Type CouplingProcess, these groups would then be unmasked or converted under standardconditions to afford the basic group.

Approximately one equivalent of the compound of Formula 23 and oneequivalent of compound of Formula 24 and one equivalent of the compoundof Formula 25 are reacted in an inert solvent. The reaction is typicallycarried out between 0° C. and 150° C. Reaction time is normally 4 to 48hours. The sequence of addition depends upon the reactivity of theindividual reagents. The intermediate addition product may be isolatedand subsequently be condensed with the second reagent. The reaction mayor may not require the addition of a catalyst. Prefered solvents for theabove reaction include acetonitrlle, DMF, DMSO, THF, toluene,isopropanol, and dichloromethane. Acids and bases as describedpreviously may be used to catalyze the above reaction.

One to five equivalents of the isocyanate, isothiocyanate, carbodiimideof Formula 28 and one to five equivalents of compound of Formula 27 arereacted in an inert solvent. The reaction is normally carried outbetween 0° C. and 150° C. Reaction time is normally 4 to 48 hours.

As outlined in Schemes 2d below, the coupling process of General Method2 may consist of an Organometallic Coupling Process.

The compound of Formula 30 (or Formula 34) is coupled with anorganometallic compound of Formula 31 (or Formula 33) (containing abasic group, or basic group precursor) in an Organometallic CouplingProcess to afford the compounds of the invention of Formula 32.

“Organometallic Coupling Processes” include “palladium-catalyzed crosscoupling reactions,” such as, Heck-type coupling reactions, Suzuki-typecoupling reactions and Stille-type coupling reactions. Otherorganometallic coupling reactions include, organocuprate couplingreactions, Grignard coupling reactions, and the like. A generaldescription of Organometallic Coupling is given in detail in AdvancedOrganic Chemistry, 4^(th) Edition, Part B, Reactions and Synthesis,Francis A. Carey and Richard J. Sundberg, Kluwer Academic/PlenumPublishers, 2000, Chapters 7 and 8, and references cited therein.

In Scheme 2d. the compound of Formula 30 (or Formula 34) is coupled withthe organometallic reagent of Formula 31 (or Formula 33) in thepresence, or absence, of a transition metal catalyst, and/or a phosphineor arsine, and/or a base in an inert solvent. Other additives, such as,copper salts, silver salts, and the like may be added. Approximately oneequivalent of the compound of Formula 30 (or Formula 34) is reacted withone to five equivalents of the compound of Formula 31 (or Formula 33)with the appropriate additives in an inert solvent. The reaction isnormally carried out between −78° C. and 200° C. for between 1 to 72hours. Analytical techniques known ot one of skill in the art are usefulfor determining completion of reaction.

Examples of “organometallic reagents” include, organomagnesium,organozinc, mixed-organocuprate, organostannane, or organoboroncompounds, and the like.

Examples of “transition metal catalysts” include, palladium and nickelcatalysts, such as, Pd(OAc)₂, Pd (PPh₃)₄, PdCl₂, Pd(PPh₃)Cl₂,Pd(OCOCF₃)₂, (CH₃C₄H₅P)₂PdCl₂, [(CH₃CH₂)₃P]₂PdCl₂, [(C₆H₁₁)₃P]₂PdCl₂,[(C₆H₅)₃P]₂PdBr₂, Ni(PPh₃)₄, (C₆H₄CH═CHCOCH═CHC₆H₅)₃Pd, and the like.

Among the above transition metal catalysts, Pd(OAc)₂, Ni(PPh₃)₄, andPd(PPh₃)₄ are preferable.

Examples of “phosphines or arsines” include, a trialkyl ortriarylphosphine or arsine, such as triisopropylphosphine,triethylphosphine, tricyclopentylphosphine, triphenylphosphine,triphenylarsine, 2-furylphosphine, tri-o-tolylphosphine,tricyclohexylphosphine, 1,2-bis(diphenylphosphino)ethane,1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane,2-(Di-t-butylphosphino)biphenyl, and the like.

Among the above “phosphines and arsines,” triphenylphosphine,tri-o-tolylphosphine, triphenylarsine, and tricyclohexylphosphine arepreferable.

Examples of “other additives” include, copper salts, zinc salts, lithiumsalts, ammonium salts and the like.

Among the above “other additives,” CuI, LiCl, and n-Bu₄N⁺Cl⁻ arepreferable. If necessary, the reaction can be carried out with a basicgroup synthon incorporated as the basic group as described previously.

As outlined in Schemes 2e below, the coupling process of General Method2 can consist of a Wittig-type Coupling Process. The compound of Formula33 (or Formula 37) is coupled with the phosphorus ylene (or ylide)reagent of Formula 34 (or Formula 36) to afford the compounds of Formula35 of the invention. A general description of Wittig-type CouplingReactions is given in detail in general reference texts such as AdvancedOrganic Chemistry, 4^(th) Edition, Part B, Reactions and Synthesis,Francis A. Carey and Richard J. Sundberg, Kluwer Academic/PlenumPublishers, 2000, Chapter 2, and references cited therein.

The compound of Formula 33 (or Formula 37) is coupled with thephosphorus ylene (or ylide) reagent of Formula 34 (or Formula 36) in thepresence, or absence, of a base in an inert solvent to form thecompounds of the invention i.e., Formula 35. Other additives, such as,lithium salts, sodium salts, potassium salts, and the like may be added.Approximately one to five equivalents of the compound of Formula 33 (orFormula 37) is reacted with one to five equivalents of the compound ofFormula 34 (or Formula 36) with the appropriate additives in an inertsolvent. The reaction is normally carried out between −78° C. and 120°C. for between 2 to 72 hours. The Wittig reaction product may be reducedto form other compounds of the invention using reducing agents known toone of skill in the art and/or described previously. Preferred bases forthe above organometallic reactions include sodium hydride, DBUJ,potassium t-butoxide, and lithium hexamethyldisilazide.

General Method 3: Coupling of the Ar² and Ar³ Groups

The compounds of Formula 3 can be prepared by the General Method 3,described in General Scheme 3, via coupling of the compounds of Formula38 with a compound of Formula 39. An example of the General Method 3 isa Aryl Coupling Process (Scheme 3a). The aryl-coupling reaction iscarried out in accordance with known methods, or analogous methodsthereto, such as those described in the general reference textsdiscussed previously.

The compound of Formula 44 (or Formula 45) is coupled with anorganometallic compound of Formula 43 (or Formula 46) in an ArylCoupling Process to afford the compounds of the invention of Formula 3.

The compound of Formula 44 (or Formula 45) is coupled with theorganometallic reagent of Formula 43 (or Formula 46) in the presence, orabsence, of a transition metal catalyst, and (or) a phosphine or arsine,and (or) a base in an inert solvent. Other additives, such as, coppersalts, silver salts, and the like may be added. Approximately oneequivalent of the compound of Formula 44 (or Formula 45) is reacted withone to five equivalents of the compound of Formula 43 (or Formula 46)with the appropriate additives in an inert solvent. The reaction isnormally carried out between −78° C. and 200° C. for between 1 to 72hours. Examples of “organometallic reagents”, “transition metalcatalysts” “phosphines or arsines” “other additives” and “base” havebeen described previously.

General Method 4: Heterocycle Formation

The compounds of Formula 3 can be prepared by the General Method 4,described in General Scheme 4, via reaction of the compound of Formula47 containing a coupling group with a compound of Formula 48 containinga coupling group, wherein during the course of the coupling reaction thecoupling groups form the 6-membered ring heterocycle between the linkerL¹ and the phenyl ring. Ar¹, L¹, Ar², L², and basic group are defined asabove. Examples of heterocyclic ring forming reactions are given inComprehensive Heterocyclic Chemistry, Volumes 1-8, A. P. Katritzky andC. W. Rees Eds, Pergamon Press, 1984; Heterocyclic Chemistry, 3^(rd) Ed,Thomas L. Gilchrist, Addison-Wesley-Longman Ltd, 1997; An Introductionto the Chemistry of Heterocyclic Compounds, 3^(rd) Ed, R. M. Acheson,Wiley Interscience, 1976; etc, and references cited therein. Specificexamples of the General Method 4 include an Oxadiazole Process (Schemes4a and 4b), a Thiadiazole Process (Scheme 4c), and an Oxazole Process(Scheme 6 a-e).

If necessary, the reaction can be carried out with a basic group synthonincorporated as the basic group, i.e., a group that could readily beconverted to a basic group by methods known to one skilled in the art.Basic group synthons would include, but not be limited to, halogen,protected amine, nitrile, aldehyde, and the like. Following theHeterocycle Formation Process, these groups would then be unmasked orconverted under standard conditions to afford the basic group.

General Method 5: Coupling of Tile Linker Group L1

The compounds of Formula 3 can be prepared by the General Method 5,described in General Scheme 5, via reaction of the coupling group ofFormula 49 with a coupling group of Formula 50, where during the courseof the coupling reaction the coupling groups are retained, or lost, toform the linker L¹ between the 6-membered ring carbocyclic orheterocyclic group and Ar¹. Ar¹, L¹, Ar², L², and basic group aredefined as above. La is defined as a group that when the couplingprocess occurs results in the formation of the linker L² defined above.Examples of the General Method 5 are an Ether/Thioether AlkylationProcess (Scheme 5a), an Acylation/Sulfonylation Process Process (Scheme5b), an Urea/Thiourea/Guanadine Coupling Process (Scheme 5c1, 5c2, 5c3),an Organometallic Process (Scheme 5d), and a Wittig-type Coupling(Scheme 5e).

If necessary, the reactions below may be carried out with a basic groupsynthon incorporated as the basic group, as described previously.Following the Coupling of the Linker Group (L¹) Process, these groupswould then be unmasked or converted under standard conditions to affordthe basic group.

As outlined in Scheme 5a below, the coupling process of General Method 5can consist of an Ether/Thioether Alkylation Process. Nucleophilicdisplacement by an alcohol or thiol-containing compound of Formula 51(or Formula 55) with a compound of Formula 52 (or Formula 54) containinga leaving group affords the ether and thioether compounds of Formula 53of the invention. The processes are analogous to the process describedfor the General Method 2, described in Scheme 2a, and carried out inaccordance with the above method.

As outlined in Scheme 5b below, the coupling process of General Method 5can consist of an Acylation/Sulfonylation Process. Acylation orsulfonylation of an alcohol or amine compound of Formula 57 with acarboxylic acid or sulfonic acid compound of Formula 56, affords theester, amide, sulfonic ester, or sulfonamide compounds of Formula 58.Alternatively, acylation or sulfonylation of an alcohol or aminecompound of Formula 59 with a carboxylic acid or sulfonic acid compoundof Formula 60 affords the ester, amide, sulfonic ester, or sulfonamidecompounds of Formula 61. The processes are analogous to the processdescribed for the General Method 2, described in Scheme 2b, and arecarried out in accordance with the above method.

As outlined in Schemes 5c1, 5c2, and 5c3, below, the coupling process ofGeneral Method 5 can consist of a Urea/Thiourea/Guanidine/Carbamate-TypeCoupling Process to afford the compounds of Formula 64, 68, and 71 ofthe invention. The processes are analogous to the processes describedfor the General Method 2, described in Schemes 2c1, 2c2, and 2c3, andare carried out in accordance with the above method.

As outlined in Schemes 5d below, the coupling process of General Method5 can consist of a Organometallic Coupling Process. The compound ofFormula 73 (or Formula 74) is coupled with an organometallic compound ofFormula 72 (or Formula 75) in an Organometallic Coupling Process toafford the compounds of Formula 3 of the invention. The processes areanalogous to the processes described for the General Method 2, describedin Scheme 2d, and are carried out in accordance with the above methods.

As outlined in Schemes 5e below, the coupling process of General Method2 can consist of a Wittig-type Coupling Process. The compound of Formula76 (or Formula 80) is coupled with the phosphorus ylene (or ylide)reagent of Formula 77 (Formula 79) to afford the compounds of Formula 78of the invention. The processes are analogous to the processes describedfor the General Method 2, described in Scheme 2e, and are carried out inaccordance with the above methods.

Demonstration of Function

In order to demonstrate that compounds of the present invention have thecapacity to bind to and inhibit the function of MCHR1, binding andfunctional assays were established. All ligands, radioligands, solventsand reagents employed in these assays are readily available fromcommercial sources or can be readily prepared by those skilled in theart.

The full-length cDNA for human MCHR1 was cloned from a human adult braincDNA library (Edge Biosystems, Cat. 38356) by standard polymerase chainreaction (PCR) methodology employing the following primers: sense,5′-GCCACCATGGACCT GGAAGCCTCGCTGC-3′; anti-sense,5′-TGGTGCCCTGACTTGGAGGTGTGC-3′. The PCR reaction was performed in afinal volume of 50 μL containing 5 μL of a 10× stock solution of PCRbuffer, 1 μL of 10 mM dNTP mixture (200 μM final), 2 μL of 50 mM Mg(SO₄)(2 mM final), 0.5 μL of 20 μM solutions of each primer (0.2 μM final), 5μL of template cDNA containing 0.5 ng DNA, 0.5 μL of Platinum Taq HighFidelity DNA polymerase (Gibco Life Technologies) and 36 μL of H₂O. PCRamplification was performed on a Perkin Elmer 9600 thermocycler. Afterdenaturation for 90 sec at 94° C., the amplification sequence consistingof 94° C. for 25 sec, 55° C. for 25 sec and 72° C. for 2 min wasrepeated 30 times, followed by a final elongation step at 72° C. for 10min. The desired PCR product (1.1 Kb) was confirmed by agarose gelelectrophoresis and the band was extracted from the gel by Geneclean(Bio101) following the manufacturer's instructions. Followingextraction, the cDNA fragment was cloned into pCR2.1-TOPO plasmid(Invitrogen) to confirm the identity and sequence.

In order to generate cell lines stably expressing MCHR1, the insert wasthen subcloned into the Xba I and Not I sites of pcDNA(+)-3.1-neomycin(Invitrogen). After purification by Qiagen Maxi-prep kit (QIAGEN, Inc.),the plasmid was transfected by Fugene 6 (Roche Applied Science) intoAV12 cells that had been previously transfected with the promiscuous Gprotein G_(α15). The transfected cells were selected by G418 (800 μg/mL)for 10-14 days and single colonies were isolated from culture plates.The G418-resistant colonies were further selected for MCHR1 expressionby measuring MCH-stimulated Ca²⁺ transients with a fluorometric imagingplate reader (FLIPR, Molecular Devices).

Typically, individual clones are plated out in 96-well plates at 60,000cells per well in 100 μL of growth medium (Dulbecco's modified Eagle'smedium (DMEM), 5% fetal bovine serum, 2 mM L-glutamine, 10 mM HEPES, 1mM sodium pyruvate, 0.5 mg/ml Zeocin, and 0.5 mg/mL Geneticin). After 24hrs at 37° C., medium is removed and replaced with 50 μL of dye loadingbuffer (Hank's balanced salt solution (HBSS) containing 25 mM HEPES,0.04% Pluronate 127 and 8 μM Fluo3 Both from Molecular Probes)). After a60 min loading period at room temperature, dye loading buffer isaspirated and replaced with 100 μL of HEPES/HBBS. Plate is placed inFLIPR and basal readings are taken for 10 sec, at which point 100 μL ofbuffer containing 2 μM MCH (1 μM final) is added and measurements aretaken over 105 sec. To correct for variations between clones in numbersof cells per well, the MCH response is normalized to the responseinduced by epinephrine.

Both the ¹²⁵I-MCH binding and functional GTPγ³⁵S binding assays employedmembranes isolated from a clone designated as clone 43. Typically, cellsfrom 20 confluent T225 flasks were processed by washing the monolayersin cold phosphate-buffered saline (PBS), scraping the cells into sameand re-suspending the cell pellet in 35 mL of 250 mM Sucrose, 50 mMHEPES, pH 7.5, 1 mM MgCl₂, 24 μg/mL DNase I, and protease inhibitors (1Complete® tablet, per 50 ml of buffer prepared, Roche Diagnostics).After incubation on ice for 5 min, cells were disrupted with 20-25strokes of a Teflon/Glass homogenizer attached to an overhead motorizedstirrer, and the homogenate was centrifuged at 40,000 rpm in BeckmanType 70.1 Ti rotor. The pellets were re-suspended in 250 mM Sucrose, 50mM HEPES, pH 7.5, 1.5 mM CaCl₂, 1 mM MgSO₄ and protease inhibitors byTeflon/Glass homogenization to achieve a protein concentration of ˜3-5mg/ml (Pierce BCA assay with Bovine serum albumin as standard).

Aliquots were stored at −70° C.

Binding of compounds to MCHR1 was assessed in a competitive bindingassay employing ¹²⁵I-MCH, compound and clone 43 membranes. Briefly,assays are carried out in 96-well Costar 3632 white opaque plates in atotal volume of 200 μl containing 25 mM HEPES, pH 7.5, 10 mM CaCl₂, 2mg/ml bovine serum albumin, 0.5% dimethyl sulfoxide (DMSO), 4 μg ofclone 43 membranes, 100 pM ¹²⁵I-MCH (NEN), 1.0 mg of wheat germagglutinin scintillation proximity assay beads (WGA-SPA beads, Amersham)and a graded dose of test compound. Non-specific binding is assessed inthe presence of 1 μM unlabeled MCH. Bound ¹²⁵I-MCH is determined byplacing sealed plates in a Microbeta Trilux (Wallac) and counting aftera 5 hr delay.

IC₅₀ values (defined as the concentration of test compound required toreduce specific binding of ¹²⁵I-MCH by 50%) are determined by fittingthe concentration-response data to a 4-parameter model (max response,min response, Hill coefficient, IC₅₀) using Excel. K_(i) values arecalculated from IC₅₀ values using the Cheng-Prusoff approximation asdescribed by Cheng et al. (Relationship between the inhibition constant(K_(i)) and the concentration of inhibitor which causes 50% inhibition(IC₅₀) of an enzymatic reaction, Biochem. Pharmacol., 22: 3099-3108(1973)). The K_(d) for ¹²⁵I-MCH is determined independently from asaturation binding isotherm.

Functional antagonism of MCH activity is assessed by measuring theability of test compound to inhibit MCH-stimulated binding of GTPγ³⁵S toclone 43 membranes. Briefly, assays are carried out in Costar 3632 whiteopaque plates in a total volume of 200 μl containing 25 mM Hepes, pH7.5, 5 mM MgCl₂, 10 μg/ml saponin, 100 mM NaCl, 3 μM GDP, 0.3 nMGTPγ³⁵S, 40 nM MCH (approximately equal to EC₉₀), 20 μg of clone 43membranes, 1.0 mg of wheat germ agglutinin scintillation proximity assaybeads (WGA-SPA beads, Amersham) and a graded dose of test compound. Theplates are sealed and left for 16-18 hrs at 4° C. After a 1 hr delay toallow plates to equilibrate to ambient temperature, bound GTPγ³⁵S isdetermined by counting in a Microbeta Trilux (Wallac).

IC₅₀ values (defmed as the concentration of test compound required toreduce MCH-stimulated GTPγ³⁵S binding by 50%) are determined by fittingthe concentration-response data to a 4-parameter model (max response,min response, Hill coefficient, IC₅₀) using Excel. K_(b) values arecalculated from IC₅₀ values using a modification of the Cheng-Prusoffapproximation as described by Leff and Dougal (Further concerns overCheng-Prusoff analysis, Trends Pharmacol. Sci. 14: 110-112 (1993)) afterverifying competitive antagonism by Schild analysis. The EC₅₀ for MCHalone is determined independently. The MCHR1 binding activities ofrepresentative examples of compounds of the invention (tested induplicate) are shown in Table 1 TABLE 1 Compound of Example #MOLSTRUCTURE MCHr Binding Ki (uM) 1

5.04 4

11.7 2

7.52 24

6.13 23

7.2 6

10.1 3

10.67 25

6.89 14

1.47 15

1.95 4

11.73 20

11.37 21

8.55 22

10.84 13

8.76 16

8.96 9

16.3Utilities

As an antagonist of the MCH receptor-1 binding, a compound of thepresent invention is useful in treating conditions in human andnon-human animals in which the the MCH receptor-1 has been demonstratedto play a role. The diseases, disorders or conditions for whichcompounds of the present invention are useful in treating or preventinginclude, but are not limited to, diabetes mellitus, hyperglycemia,obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,atherosclerosis of coronary, cerebrovascular and peripheral arteries,gastrointestinal disorders including peptid ulcer, esophagitis,gastritis and duodenitis, (including that induced by H. pylori),intestinal ulcerations (including inflammatory bowel disease, ulcerativecolitis, Crohn's disease and proctitis) and gastrointestinalulcerations, neurogenic inflammation of airways, including cough,asthma, depression, prostate diseases such as benign prostatehyperplasia, irritable bowel syndrome and other disorders needingdecreased gut motility, diabetic retinopathy, neuropathic bladderdysfunction, elevated intraocular pressure and glaucoma and non-specificdiarrhea dumping syndrome. Compounds of the present invention have alsoshown some affinity for the R2 isoform of MCHR. In treating humans, thecompounds of the present invetion are useful in treating and/orpreventing obesity, excessive weight gain and diseases related to orexercerbated b excessive weight gain.

In treating non-human, non-companion animals, the compounds of thepresent invention are useful for reducing weight gain and/or improvingthe feed utilization efficiency and/or increasing lean body mass.

Formulation

The compound of formula I is preferably formulated in a unit dosage formprior to administration. Therefore, yet another embodiment of thepresent invention is a pharmaceutical formulation comprising a compoundof formula I and a pharmaceutical carrier.

The present pharmaceutical formulations are prepared by known proceduresusing well-known and readily available ingredients. In making theformulations of the present invention, the active ingredient (compoundof formula I) will usually be mixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of aliquid, tablet, capsule, sachet, paper or other container. When thecarrier serves as a diluent, it may be a solid, semisolid or liquidmaterial which acts as a vehicle, excipient or medium for the activeingredient. Thus, the compositions can be in the form of tablets, pills,powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,solutions, syrups, aerosol (as a solid or in a liquid medium), soft andhard gelatin capsules, suppositories, sterile injectable solutions andsterile packaged powders. Some examples of suitable carriers,excipients, and diluents include lactose, dextrose, sucrose, sorbitol,mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyland propylhydroxybenzoates, talc, magnesium stearate and mineral oil.The formulations can additionally include lubricating agents, wettingagents, emulsifying and suspending agents, preserving agents, sweeteningagents or flavoring agents. The compositions of the invention may beformulated so as to provide quick, sustained or delayed release of theactive ingredient after administration to the patient by methods knownto one of the art.

FORMULATION EXAMPLES Formulation 1 Tablets

Ingredient Quantity (mg/tablet) Active Ingredient  5-500 Cellulose,microcrystalline 200-650 Silicon dioxide, fumed  10-650 Stearate acid 5-15

The components are blended and compressed to form tablets.

Formulation 2 Suspensions

Quantity Ingredient (mg/5 ml) Active Ingredient 5-500 mg Sodiumcarboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10ml Flavor q.v. Color q.v. Purified water to 5 ml

The medicament is passed through a No. 45 mesh U.S. sieve (approximately355 micron opening) and mixed with the sodium carboxymethyl celluloseand syrup to form a smooth paste. The benzoic acid solution, flavor, andcolor are diluted with some of the water and added, with stirring.Sufficient water is then added to produce the required volume.

Formulation 3 Intravenous Solution

Ingredient Quantity Active Ingredient 25 mg Isotonic saline 1,000 ml

The solution of the above ingredients is intravenously administered to apatient at a rate of about 1 ml per minute.

Dose

The specific dose administered is determined by the particularcircumstances surrounding each situation. These circumstances includebut are not limited to, the route of administration, the prior medicalhistory of the recipient, the pathological condition or symptom beingtreated, the severity of the condition/symptom being treated, and theage and sex of the recipient. However, it will be understood that thetherapeutic dosage administered will be determined by the physician inthe light of the relevant circumstances, or by the vetrinarian fornon-human recipients.

Generally, an effective minimum daily dose of a compound of formula I isabout 5, 10, 15, 40 or 60 mg. Typically, an effective maximum dose isabout 500, 100, 60, 50, or 40 mg. Most typically, the dose rangesbetween 5 mg and 60 mg. The exact dose may be determined, in accordancewith the standard practice in the medical arts of “dose titrating” therecipient; that is, initially administering a low dose of the compound,and gradually increasing the dose until the desired therapeutic effectis observed.

Route of Administration

The compounds may be administered by a variety of routes including theoral, rectal, transdermal, subcutaneous, topical, intravenous,intramuscular or intranasal routes.

Combination Therapy

A compound of formula I may be used in combination with other drugs ortherapies that are used in the treatment/prevention/suppression oramelioration of the diseases or conditions for which compounds offormula I are useful. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of formula I. When a compound of formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalunit dosage form containing such other drugs in addition to the compoundof formula I is preferred. Accordingly, the pharmaceutical compositionsof the present invention include those that also contain one or moreother active ingredients, in addition to a compound of formula I.Examples of other active ingredients that may be combined with acompound of formula I, and either administered separately or in the samepharmaceutical compositions, include, but are not limited to:

-   -   (a) insulin sensitizers including (i) PPARγ agonists such as the        glitazones (e.g. troglitazone, pioglitazone, englitazone,        MCC-555, BRL49653 and the like), and compounds disclosed in        WO97/27857, 97/28115, 97/28137 and 97/27847;        -   (ii) biguanides such as metformin and phenformin;    -   (b) insulin or insulin mimetics;    -   (c) sulfonylureas such as tolbutamide and glipizide;    -   (d) alpha-glucosidase inhibitors (such as acarbose);    -   (e) cholesterol lowering agents such as        -   i. HMG-CoA reductase inhibitors (lovastatin, simvastatin and            pravastatin, fluvastatin, atorvastatin, and other statins),        -   ii. sequestrants (cholestyramine, colestipol and a            dialkylaminoalkyl derivatives of a cross-linked dextran),        -   iii. nicotinyl alcohol nicotinic acid or a salt thereof,        -   iv. proliferator-activator receptor a agonists such as            fenofibric acid derivatives (gemfibrozil, clofibrat,            fenofibrate and benzafibrate),        -   v. inhibitors of cholesterol absorption for example            β-sitosterol and (acyl CoA:cholesterol acyltransferase)            inhibitors for example melinamide,        -   vi. probucol,        -   vii. vitamin E, and        -   viii. thyromimetics;    -   (f) PPARδ agonists such as those disclosed in WO97/28149;    -   (g) antiobesity compounds such as fenfluramine,        dexfenfluramrine, phentermine, sibutramine, orlistat, and other        β₃ adrenergic receptor agonists;    -   (h) feeding behavior modifying agents such as neuropeptide Y        antagonists (e.g. neuropeptide Y5) such as those disclosed in WO        97/19682, WO 97/20820, WO 97/20821, WO 97/20822 and WO 97/20823;    -   (i) PPARα agonists such as described in WO 97/36579 by Glaxo;    -   (j) PPARγ antagonists as described in WO97/10813; and    -   (k) serotonin reuptake inhibitors such as fluoxetine and        sertraline.

Experimental

The following examples are only illustrative of the prepration protocolsand Applicants' ability to prepare compounds of the present inventionbased on the schemes presented or modifications thereof. The examplesare not intended to be exclusive or exhaustive of compounds made orobtainable.

General Preparations Preparation of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid from4-methylbenzeneboronic acid and ethyl 3-bromobenzoate

a) 4′-Methyl-biphenyl-3-carboxylic acid ethyl ester

A solution of 4-methylbenzeneboronic acid (4.45 g, 32.75 mmol, 1.5 eq.)and ethyl 3-bromobenzoate (5.0 g, 21.83 mmol, 1 eq.) in THF (100 mL) wastreated with 2M aqueous sodium carbonate (24 mL, 48.03 mmol, 2.2 eq.)followed by palladium(II) acetate (0.49 g, 2.18 mmol, 10 mol %),triphenylphosphine (2.52 g, 9.59 mmol, 4.4×Pd eq.), and copper(I) iodide(catalyst, 0.13 g, 0.68 mmol) as solids. The solution was then heated to65° C. overnight.

The dark reaction was cooled and diluted with water and extracted 2×200mL with EtOAc. The organic layers were combined, dried over MgSO₄,filtered, and the solvent removed in vacuo leaving a dark oil.

The oil was purified by preparative HPLC (Waters LC-2000) using agradient starting with 100% hexane and going to 5% EtOAc in hexane over30 minutes. Fractions containing the product were pooled and the solventremoved leaving 4′-methyl-biphenyl-3-carboxylic acid ethyl ester as afaint yellow oil (5.01 g, 95% yield).

¹H NMR (DMSO-d6) δ8.17 (m, 1H), 7.92 (m, 2H), 7.61 (m, 3H), 7.30 (d, 2H,J=8 Hz), 4.35 (q, 2H, 7 Hz), 2.36 (s, 3H), and 1.35 (t, 3H, J=7 Hz). IR(CHCl₃, cm⁻¹)1715, 1369, 1310, 1300, 1249, 1110. MS (ES⁺)m/z 241. Anal.Calcd for C₁₆H₁₆O₂ C, 79.97; H, 6.71; N, 0.00. Found C, 79.84; H, 6.48;N, 0.14.

4′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester

A solution of 4′-methyl-biphenyl-3-carboxylic acid ethyl ester (2.5 g,10.4 mmol, 1 eq.) in CCl₄ (150 mL) was treated with N-bromosuccinimide(2.78 g, 15.6 mmol, 1.5 eq.) in a round bottom flask equipped with astir bar, septum, and N₂ line with bubbler. The yellow solution washeated to 50° C. with a heating mantle. After the temperature of thereaction had reached 50° C., 2,2′-azobisisobutyronitrile (0.17 g, 1.04mmol, 10%) was added as a solid and the reaction heated to 76° C.

After 2 hours at 76° C., the reaction was diluted with water and theorganic layer removed. The aqueous layer was extracted with CH₂Cl₂. Theorganic layers were combined, dried over MgSO₄, filtered, and thesolvent removed in vacuo leaving a yellow oil.

The oil was purified by preparative HPLC (Waters LC-2000) using agradient starting with 100% hexane and going to 10% EtOAc in hexane over30 minutes. Fractions containing the product were pooled and the solventremoved in vacuo leaving 4′-bromomethyl-biphenyl-3-carboxylic acid ethylester as a yellow oil (3.11 g, 94% yield).

¹H NMR (DMSO-d6) δ 8.22-7.5 (m, 8H), 4.81 (s, 2H), 4.36 (q, 2H, J=7 Hz),1.36 (t, 3H, J=7 Hz). MS (FD⁺) m/z 320, 318. Anal. Calcd for C₁₆H₁₅BrO₂C, 60.21; H, 4.74; N, 0. Found C, 58.08; H, 4.47; N, 0.14.

c) 4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester

A solution of 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester(3.05 g, 9.55 mmol, 1.02 eq.) in anhydrous DMF (50 mL) was treated withsolid potassium carbonate (3.88 g, 28.08 mmol, 3 eq.) followed by2-mercaptoethanol (0.73 g, 0.66 mL, 9.36 mmol, 1 eq.). The reaction wasallowed to stir at room temperature overnight.

The reaction was diluted with water and extracted 2×100 mL with EtOAc.The organic layers were combined and washed with 50% brine. The organiclayer was collected, dried over MgSO₄, filtered, and the solvent removedin vacuo leaving a yellow oil.

Purified the oil by preparative HPLC (Waters LC-2000) using a gradientstarting with 5% EtOAc in hexane and going to 40% EtOAc in hexane over30 minutes. Fractions containing the product were pooled and the solventremoved in vacuo leaving4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester as a yellow oil (1.39 g, 47% yield).

¹H NMR (DMSO-d6) δ 8.18 (m, 1H), 7.95 (m, 2H), 7.65 (m, 3H), 7.44 (m,2H), 4.79 (t, 1H, J=6 Hz), 4.35 (q, 2H, J=7 Hz), 3.82 (s, 2H), 3.54 (q,2H, J=7 Hz), 2.51 (t, 2H, J=7 Hz), 1.35 (t, 3H, J=7 Hz). IR (CHCl₃,cm⁻¹) 3501, 3016, 1714, 1369, 1309, 1243, 1272, 1110, 1058, 1044. MS(FD₊) m/e 316. Anal. Calcd for C₁₈H₂₀O₃S C, 68.33; H, 6.37; N, 0. FoundC, 66.76; H, 6.04; N, 0.19.

d) 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester

4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester (1.35 g, 4.27 mmol, 1 eq.) was dissolved in anhydrous THF (50 mL)with triphenyphosphine (1.57 g, 5.98 mmol, 1.4 eq.) and phenol (0.56 g,5.98 mmol, 1.4 eq.). To this solution, diisopropyl azidocarboxylate(1.21 g, 1.18 mL, 5.98 mmol, 1.4 eq.) was added dropwise via syringeover 5 minutes. After addition was complete, The reaction was stirred atroom temperature for 2 hours and then at 50° C. for another hour.

The reaction was diluted with EtOAc and washed with 0.5M aqueous NaOH.The organic layer was collected, dried over MgSO₄, filtered, and thesolvent removed in vacuo leaving a yellow oil.

The oil was purified via silica gel flash chromatography using 15% EtOAcin hexane as the mobile phase. Fractions containing the product werepooled and the solvent removed in vacuo leaving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester (1.23 g, 73% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 8.18 (m, 1H), 7.94 (m, 2H), 7.65 (m, 3H), 7.47 (d,2H, J=8 Hz), 7.27 (m, 2H), 6.91 (m, 3H), 4.35 (q, 2H, J=7 Hz), 4.11 (t,2H, J=7 Hz), 3.91 (s, 2H), 2.80 (t, 2H, J=7 Hz), 1.35 (t, 3H, J=7 Hz).IR (CHCl₃, cm⁻¹) 1714, 1601, 1498, 1308, 1244, 1110. MS(FD⁺) m/e 392.Anal. Calcd for C₂₄H₂₄O₃S C, 73.44; H, 6.16; N. 0. Found C, 70.51; H,6.03; N, 0.91.

e) 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid

Dissolved 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acidethyl ester (1.61 g, 4.10 mmol, 1 eq.) in 30% aqueous THF (25 mL) andtreated with lithium hydroxide (0.29 g, 12.3 mmol, 3 eq.). The reactionwas then stirred overnight at 60° C.

Diluted the reaction with water and acidified to pH 2 with 1 M HCl.Extracted the reaction with 2×150 mL Et₂O. The organic layers werecombined, dried over MgSO₄, filtered, and the solvent removed in vacuoleaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(1.49 g, 100% yield) as abrown oil which crystallized on standing.

1H NMR (DMSO-d6) δ 13.12 (s, 1H), 8.18 (m, 1H), 7.92 (m, 2H), 7.62 (m,3H), 7.43 (m, 2H), 7.25 (m, 2H), 6.91 (m, 3H), 4.12 (t, 2H, J=7 Hz),3.95 (s, 2H), 2.81 (t, 2H, J=7 Hz). IR (CHCl₃, cm⁻¹) 3062, 2926, 2874,2657, 1696, 1601, 1497, 1243, 1226, 1173, 1033. MS (ES⁻) m/e 363. Anal.Calcd for C₂₂H₂₀O₃S C, 72.50; H, 5.53; N, 0. Found C, 72.10; H, 5.54; N,0.15.

Example 1 Preparation of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylicacid(3-dimethylamino-propyl)-amide oxalate

A solution of 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylicacid (0.91 g, 2.5 mmol, 1 eq.) in anhydrous THF (10 mL) was treated with1,1′-carbonyldiimidazole (0.41 g, 2.55 mmol, 1.02 eq.) and the resultingsolution heated to 60° C. for 25 minutes.

The solution was then allowed to cool and the3-(dimethylamino)propylamine (0.31 g, 0.38 mL, 3 mmol, 1.2 eq.) wasadded via syringe. The reaction was allowed to stir at room temperature.

After 2 hours, the reaction was diluted with water and extracted with2×150 mL EtOAc. The organic layers were combined, dried over MgSO₄,filtered, and the solvent removed in vacuo leaving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide (0.97 g, 87% yield) as a yellow oil.

Dissolved 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylicacid(3-dimethylamino-propyl)-amide (0.48 g, 1.07 mmol, 1 eq.) in acetone(10 mL) and treated the solution dropwise with oxalic acid(0.12 g, 1.28mmol, 1.2 eq.) in acetone (5 mL). Added Et₂O until cloudy and thenplaced in the freezer to induce crystallization. The resulting whitesolid was collected by filtration and washed with Et₂O to give4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylicacid(3-dimethylamino-propyl)-amide oxalate (0.2217 g).

¹H NMR (DMSO-d6) δ 8.74 (br t, 1H), 8.12 (s, 1H), 7.83 (m, 2H), 7.69 (d,2H, J=8 Hz), 7.56 (t, 1H, J=8 Hz), 7.47 (d, 2H, J=8 Hz), 7.28 (t, 2H,J=8 Hz), 6.92 (m, 3H), 4.12 (t, 2H, J=7 Hz), 3.92 (s, 2H), 3.35 (br,2H), 3.04 (br, 2H), 2.80 (t, 2H, J=7 Hz), 2.73 (s, 6H), 1.89 (br, 2H).IR (KBr, cm⁻¹) 3357, 3042, 1718, 1644, 1601, 1542,1243. MS (ES⁺) m/e449. Analysis calcd for C₂₉H₃₄N₂O₆S C, 64.66; H, 6.36; N, 5.20. Found C,64.11; H, 6.25; N, 5.20. Analytical HPLC 94.3%. MP 132-133.5° C.

Example 2 Preparation of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate

Prepared in the same manner as described for example 1. A solution of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(0.68 g,1.87 mmol, 1 eq.) was treated with 1,1′-carbonyldiimidazole (0.31 g,1.91 mmol, 1.02 eq.) and warmed as described. The reaction was allowedto cool and then treated with N′,N-dimethylethylenediamine (0.20 g, 2.24mmol, 1.2 eq.). The reaction was treated as described in example 1 togive 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylicacid(2-dimethylamino-ethyl)-amide (0.76 g, 94% yield) as a faint yellowoil.

The free base was converted to the oxalate salt as described in example1 using 0.20 g of oxalic acid giving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate (0.5584 g) as a white solid.

¹H NMR (DMSO-d6) δ 8.89 (br, 1H), 8.14 (s, 1H), 7.84-7.26 (m, 9H), 6.91(m, 3H), 4.12 (t, 2H, J=7 Hz), 3.95 (s, 2H), 3.63 (br, 2H), 3.23 (br,2H), 2.8 (m, 8H). IR (KBr, cm⁻¹) 3423, 3270, 1721, 1637, 1600, 1585,1539, 1496, 1242, 756. MS (ES⁺) m/e 435. MS (ES⁻) m/e 433. Anal. Calcdfor C₂₈H₃₂N₂O₆S C, 64.10; H, 6.15; N, 5.34. Found C, 62.70; H, 5.78; N,5.06. Analytical HPLC 96.9% pure. MP 88-93° C.

Example 3 Preparation of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(4-dimethylamino-butyl)-amide oxalate

Prepared in the same manner as described for example 1. A solution of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (0.71 g,1.95 mmol, 1 eq.) was treated with 1,1′-carbonyldiimidazole (0.32 g,1.99 mmol, 1.02 eq.) and warmed as described. The reaction was allowedto cool and then treated with 4-dimethylaminobutylamine (0.25 g, 2.15mmol, 1.1 eq.). The reaction was treated as described in example 1 togive a faint yellow oil.

The oil was purified by silica gel chromatography by loading a CH₂Cl₂solution of the amine onto the column and running 10% 2M NH₃ in MeOH inCHCl₃ as the mobile phase. Fractions containing the product were pooledand the solvent removed in vacuo leaving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(4-dimethylamino-butyl)-amide (0.72 g, 71% yield) as a faint yellow oil.

The product was converted to the oxalate salt by adding solid oxalicacid (0.15 g) to an EtOAc solution of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(4-dimethylamino-butyl)-amide giving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(4-dimethylamino-butyl)-amide oxalate (0.4129 g) as a white solid.

¹H NMR (DMSO-d6) δ 8.66 (br, 1H), 8.10 (s, 1H), 7.81-7.25 (m, 9H), 6.91(m, 3H), 4.12 (t, 2H, J=7 Hz), 3.94 (s, 2H), 3.31 (br, 2H), 3.03 (br,2H), 2.81 (t, 2H, J=7 Hz), 2.72 (s, 6H), 1.61 (br, 4H). IR (KBr, cm⁻¹)3348, 1718, 1703, 1638, 1600, 1585, 1539, 1240. MS (ES⁺) m/e 463. MS(ES⁻) m/e 461. Anal. Calcd for C₃₀H₃₆N₂O₆S C, 65.2; H, 6.57; N, 5.07.Found C, 63.98; H, 6.60; N, 5.00. Analytical HPLC 98.1% purity. MP144-147° C.

Preparation of 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylicacid from 4-methylbenzeneboronic acid and ethyl 4-iodobenzoate

a) 4′-Methyl-biphenyl-4-carboxylic acid ethyl ester

This compound was synthesized essentially as described for4′-methyl-biphenyl-3-carboxylic acid ethyl ester. 4Methylbenzeneboronicacid (2.95 g, 21.73 mmol, 1.2 eq.) was combined with ethyl4-iodobenzoate (5.0 g, 18.11 mmol, 1 eq.) in anhydrous THF (100 mL) asdescribed. Treated this solution with 2M aqueous sodium carbonate (23.9mL, 47.81 mmol, 2.2 eq.), palladium(II) acetate (0.49 g, 2.17 mmol, 10mol %), triphenylphosphine (2.5 g, 9.55 mmol, 4.4×Pd), and copper(I)iodide (0.41 g, 2.17 mmol, 10%). The reaction was carried out and workedup as described for 4′-methyl-biphenyl-3-carboxylic acid ethyl ester toleave a dark oil.

The oil was purified by preparative HPLC (Waters LC-2000) as describedfor 4′-methyl-biphenyl-3-carboxylic acid ethyl ester leaving4′-methyl-biphenyl-4-carboxylic acid ethyl ester as a white solid (3.66g, 84% yield).

¹H NMR (DMSO-d6) δ 8.02 (d, 2H, J=9 Hz), 7.78 (d, 2H, J=9 Hz), 7.64 (d,2H, J=8 Hz), 7.31 (d, 2H, J=8 Hz), 4.34 (q, 2H, J=7 Hz), 2.36 (s, 3H),1.34 (t 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 1712, 1609, 1292, 1279, 1112, 820.MS (ES⁺) m/e 241. MS (ES⁻) m/e 239. Anal. calcd. for C₁₆H₁₆O₂ C, 79.97;H, 6.71; N, 0. Found C, 79.83; H, 6.77; N, 0.16.

b) 4′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester

4′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester was prepared asdescribed for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester.4′-Methyl-biphenyl-4-carboxylic acid ethyl ester (3.4 g, 14.15 mmol, 1eq.) was reacted with N-bromosuccinimide (3.27 g, 18.4 mmol, 1.3 eq.)and 2,2′-azobisisobutyronitrile (0.12 g, 0.71 mmol, 5 mol %) in carbontetrachloride (150 mL). When complete, the reaction was worked up asdescribed to produce 4′-bromomethyl-biphenyl-4-carboxylic acid ethylester (3.74 g, ,83% yield) as a yellow solid.

¹H NMR (DMSO-d6) δ 8.04 (m, 2H), 7.84 (m, 2H), 7.74 (d, 2H, J=8 Hz),7.57 (d, 2H, J=8 Hz), 4.78 (s, 2H), 4.34 (q, 2H, J=7 Hz), 1.34 (t, 3H,J=7 Hz). MS (ES+) m/e 319, 321.

c) 4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester

4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester was prepared as described for4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 4′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester (4.2 g,13.16 mmol, 1 eq.) in anhydrous DMF (100 mL) was treated with potassiumcarbonate (5.46 g, 39.48 mmol, 3 eq.) and 2-mercaptoethanol (1.23 g,15.79 mmol, 1.2 eq.). When the reaction was complete, the reaction wasworked up as described leaving a yellow oil upon removal of the solvent.

The oil was purified via silica gel flash chromatography using a stepgradient of EtOAc in hexanes as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester (2.41 g, 58% yield) as a white solid.

¹H NMR (DMSO-d6) δ 8.03 (d, 2H, J=8 Hz), 7.82 (d, 2H, J=8 Hz), 7.70 (d,2H, J=8 Hz), 7.45 (d, 2H, J=8 Hz), 4.78 (t, 1H, J=6 Hz), 4.33 (q, 2H,J=7 Hz), 3.81 (s, 2H), 3.52 (q, 2H, J=7 Hz), 2.50 (br, 2H), 1.34 (t, 3H,J=7 Hz). IR (CHCl₃, cm⁻¹) 3599, 3506 (br), 1710, 1609, 1369, 1281, 1111,1006. MS (FD)m/e 316. Anal. Calcd for C₁₈H₂₀O₃S C, 68.33; H, 6.37; N, 0.Found C, 68.14; H, 6.32; N, 0.19.

d) 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester

4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester was prepared as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acidethyl ester (3.11 g, 9.83 mmol, 1 eq.) in anhydrous THF (100 mL) wastreated with phenol (1.29 g, 13.76 mmol, 1.4 eq.), triphenylphosphine(3.61 g, 13.76 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (2.78 g,2.71 mL, 13.76 mmol, 1.4 eq.) as described. When the reaction wascomplete, the reaction was worked up and the product purified via silicagel flash chromatography leaving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid ethyl ester(3.82 g, 99% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 8.03 (d, 2H, J=8 Hz), 7.82 (d, 2H, J=8 Hz), 7.70 (d,2H, J=8 Hz), 7.48 (d, 2H, J=8 Hz), 7.27 (m, 2H), 6.93 (m, 3H), 4.33 (q,2H, J=7 Hz), 4.11 (t, 2H, J=7 Hz), 3.91 (s, 2H), 2.80 (t, 2H, J=7 Hz),1.34 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 1710, 1609, 1601, 1497, 1369,1311, 1281, 1179, 1173, 1111, 1030, 1007. MS (FD) m/e 392. Anal. Calcdfor C₂₄H₂₄O₃S C, 73.44; H, 6.16; N, 0. Found C, 71.92; H, 6.15; N, 0.51.

e) 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid

4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid wasprepared as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid.4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester (3.75 g, 9.55 mmol, 1 eq.) in 30% aqueous THF was reacted withlithium hydroxide (0.69 g, 28.65 mmol, 3 eq.). When complete, thereaction was worked up as described leaving a light yellow solid whichwas recrystallized from acetone/diethyl ether to afford4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2.28 g,65% yield) as a light yellow solid.

¹H NMR (DMSO-d6) δ 12.9 (s, 1H), 8.02 (m, 2H), 7.76 (m, 4H), 7.47 (m,2H), 7.29 (m, 2H), 6.94 (m, 3H), 4.11 (t, 2H, J=7 Hz), 3.91 (s, 2H),2.80 (t, 2H, J=7 Hz). IR (KBr, cm⁻¹) 3411, 1685, 1676, 1603, 1608, 1497,1427, 1302, 1290, 1246, 1234, 858, 776, 754. MS (ES⁻) m/e 363.Analytical composition calculated for C₂₂H₂₀O₃S C, 72.50; H, 5.53; N, 0.Found C, 73.95; H, 5.70; N, 0.21.

Example 4 Preparation of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate

4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide was prepared as described in example 1.4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.8 g,2.19 mmol, 1 eq.) in THF was treated with 1,1′-carbonyldiimidazole (0.36g, 2.23 mmol, 1.02 eq.). The resulting acyl imidazole was then treatedwith N,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq). Whencomplete, the reaction was worked up and the resulting yellow oilpurified as described in example 3 to give4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide (0.82 g, 86% yield) as a yellow oil.

The free base was converted to the oxalate as by adding a solution ofoxalic acid (0.20 g, 1.2 eq.) in EtOAc dropwise to an EtOAc solution ofthe amine giving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate (0.84 g) as a white solid.

¹H NMR (DMSO-d6) δ 8.78 (t, 1H, J=5 Hz), 7.96 (d, 2H, J=8 Hz), 7.78 (d,2H, J=8 Hz), 7.70 (d, 2H, J=8 Hz), 7.46 (d, 2H, J=8 Hz), 7.27 (m, 2H),6.93 (m, 3H), 4.12 (t, 2H, J=7 Hz), 3.91 (s, 2H), 3.62 (m, 2H), 3.21 (t,2H, J=7 Hz), 2.79 (m, 8H). IR (KBr, cm⁻¹) 3436, 1718, 1654, 1605, 1534,1494. MS (ES⁺) m/e 435. Analytical composition calculated forC₂₈H₃₂N₂O₆S C, 64.10; H, 6.15; N, 5.34. Found C, 62.91; H, 6.03; N,5.26. Analytical HPLC 98.1% purity. MP 122-126° C.

Example 5

Preparation of 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylicacid (3-dimethylamino-propyl)-amide hydrochloride

4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(3-dimethylamino-propyl)-amide was prepared as described in example 1.4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.6 g,1.65 mmol, 1 eq.) in THF was treated with 1,1′-carbonyldiimidazole (0.27g, 1.68 mmol, 1.02 eq.). The resulting acyl imidazole was then treatedwith 3-(dimethylamino)propylamine (0.20 g, 1.98 mmol, 1.2 eq.). Whencomplete, the reaction was worked up and the resulting yellow oilpurified as described in example 3 to give4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid(3-dimethylamino-propyl)-amide (0.55 g, 74% yield) as a white solid.

The free base was converted to the hydrochloride salt by adding HCl(0.38 mL of 4 M HCl in 1,4-dioxane) dropwise to a CH₂Cl₂/Et₂O solutionof the amine. Addition of more Et₂O with vigorous stirring produced4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(3-dimethylamino-propyl)-amide hydrochloride (0.43 g) as a yellow solid.

¹H NMR (DMSO-d6) δ 8.75 (t, 1H, J=5 Hz), 7.97 (d, 2H, J=8 Hz), 7.77 (d,2H, J=8 Hz), 7.70 (d, 2H, J=8 Hz), 7.46 (d, 2H, J=8 Hz), 7.27 (m, 2H),6.93 (m, 3H), 4.12 (t, 2H, J=7 Hz), 3.91 (s, 2H), 3.36 (m, 2H), 3.09 (m,2H), 2.80 (t, 2H, J=7 Hz), 2.75 (s, 6H), 1.93 (m, 2H). IR (KBr, cm⁻¹)3432, 3311, 1652, 1601, 1540, 1495, 1303, 1242. MS (ES⁺) m/e 449. MS(ES⁻) m/e 447. Analytical composition calculated for C₂₇H₃₃CIN₂O₂S C,66.85; H, 6.86; N, 5.77. Found C, 66.06; H, 6.69; N, 5.84. AnalyticalHPLC 100% purity. MP 112-115° C.

Example 6 Preparation of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(4-dimethylamino-butyl)-amide oxalate

4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(4-dimethylamino-butyl)-amide was prepared as described in example 1.4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.8 g,2.19 mmol, 1 eq.) in THF was treated with 1,1′-carbonyldiimidazole (0.36g, 2.23 mmol, 1.02 eq.). The resulting acyl imidazole was then treatedwith 4-dimethylaminobutylamine (0.28 g, 2.41 mmol, 1.1 eq.). Whencomplete, the reaction was worked up to leave a yellow oil (0.72 g, 71%yield) which solidified on standing. The free base was converted to theoxalate as described in example 3 to give4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(4-dimethylamino-butyl)-amide oxalate (0.61 g) as a white solid.

¹H NMR (DMSO-d6) δ 8.78 (t, 1H, J=5 Hz), 7.93 (d, 2H, J=8 Hz), 7.76 (d,2H, J=8 Hz), 7.69 (d, 2H, J=8 Hz), 7.46 (d, 2H, J=8 Hz), 7.27 (m, 2H),6.93 (m, 3H), 4.12 (t, 2H, J=7 Hz), 3.91 (s, 2H), 3.30 (m, 2H), 3.05 (m,2H), 2.80 (t, 2H, J=7 Hz), 2.74 (s, 6H), 1.61 (m, 4H). IR (KBr, cm⁻¹)3314, 2945, 2702, 1719, 1703, 1631, 1610, 1601, 1495. MS (ES⁺) m/e 463.MS (ES⁻) m/e 461. Analytical composition calculated for C₃₀H₃₆N₂O₆S C,65.20; H, 6.57; N, 5.07. Found C, 63.48; H, 6.40; N, 5.67. AnalyticalHPLC 98.3% purity. MP 142-147° C.

Preparation of 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylicacid from 4-methylbenzeneboronic acid and ethyl 2-bromobenzoate

a) 4′-Methyl-biphenyl-2-carboxylic acid ethyl ester

4′-Methyl-biphenyl-2-carboxylic acid ethyl ester was prepared in asimilar fashion to 4′-methyl-biphenyl-3-carboxylic acid ethyl ester asdescribed. Ethyl 2-bromobenzoate (5.0 g, 21.83 mmol, 1 eq.) and4-methylbenzeneboronic acid (3.12 g, 22.92 mmol, 1.05 eq.) in THF andaqueous 2M sodium carbonate (24 mL, 2.2 eq.) were treated withpalladium(II) acetate (0.49 g, 2.18 mmol, 10 mol %), triphenylphosphine(2.52 g, 9.59 mmol, 4.4×Pd), and copper(I) iodide (0.14 g). Whencomplete, the reaction was worked up as described leaving an orange oil,which was purified, via silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled leaving 4′-methyl-biphenyl-2-carboxylic acidethyl ester (5.24 g, 99% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 7.76-7.34 (m, 5H), 7.20 (m, 3H), 4.32 and 4.04(quartets, 2H total, J=7 Hz, atropisomerism of ester), 2.35 (s, 3H),1.32 and 0.98 (triplets, 3H total, J=7 Hz, atropisomerism of ester). IR(CHCl₃, cm⁻¹) 2985, 1717, 1590, 1446, 1434, 1368, 1292, 1252, 1135,1110, 1091, 1030. MS (ES⁺) m/e 241.

b) 4′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester

4′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester was prepared in asimilar fashion to 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl esteras described. 4′-Methyl-biphenyl-2-carboxylic acid ethyl ester (5.58 g,23.22 mmol, 1 eq.) in carbon tetrachloride was treated withN-bromosuccinimide (4.96 g, 27.86 mmol, 1.2 eq.) and2,2′-azobisisobutyronitrile (0.19 g, 1.16 mmol, 5 mol %). When complete,the reaction was worked up as described to give a yellow oil. The oilwas purified by silica gel flash chromatography using 5% EtOAc in hexaneas the mobile phase. Fractions containing the product were pooled andthe solvent removed in vacuo to give4′-bromomethyl-biphenyl-2-carboxylic acid ethyl ester (7.32 g, 99%yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 7.75 (m, 1H), 7.65 (m, 2H), 7.49 (m, 3H), 7.32 (m,2H), 4.77 (s, 2H), 4.32 and 4.02 (quartets, 2H, J=7 Hz, atropisomerismof ester), 1.32 and 0.92 (triplets, 3H, J=7 Hz, atropisomerism ofester). IR (CHCl₃, cm⁻¹) 1716, 1592, 1447, 1367, 1290, 1252, 1135. MS(ES⁺) m/e 319/321 and 239 (M−Br)⁺. Analytical composition calculated forC₁₆H₁₅BrO₂ C, 60.21; H, 4.74; N, 0. Found C, 50.23; H, 3.75; N, 0.22.

c) 4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester

4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester was prepared as described for4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 4′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester (4.1 g,12.84 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol(1.2 g, 15.41 mmol, 1.2 eq.) and potassium carbonate (5.32 g, 38.52mmol, 3 eq.). When complete, the reaction was worked up and purified asdescribed for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl4-carboxylicacid ethyl ester to leave4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester (3.05 g, 42% yield) as a light yellow oil.

¹H NMR (DMSO-d6) δ 37.72 (m, 1H), 7.61 (m, 1H), 7.45 (m, 2H), 7.36 (d,2H, J=8 Hz), 7.23 (d, 2H, J=8 Hz), 4.80 (t, 1H, J=5 Hz), 4.02 (q, 2H,J=7 Hz), 3.80 (s, 2H), 3.55 (m, 2H), 2.52 (t, 2H, J=7 Hz), 0.95 (t, 3H,J=7 Hz). IR (CHCl₃, cm⁻¹) 3631, 3464, 2944 2839, 1712, 1601, 1289, 1245,1016. MS (FD⁺) m/e 316.

d) 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester

4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester was prepared as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acidethyl ester (1.65 g, 5.21 mmol, 1 eq.) was treated with phenol (0.69 g,7.29 mmol, 1.4 eq.), triphenylphosphine (1.91 g, 7.29 mmol, 1.4 eq.),and diisopropyl azidocarboxylate (1.47 g, 1.44 mL, 7.29 mmol, 1.4 eq.).When complete, the reaction was worked up and the product purified bysilica gel flash chromatography using 7.5% EtOAc in hexane as the mobilephase. Fractions containing the product were pooled and the solventremoved in vacuo leaving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester (1.40 g, 68% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 7.72 (m, 1H), 7.60 (m, 1H), 7.42 (m, 4H), 7.26 (m,4H), 6.93 (m, 3H), 4.13 (t, 2H, J=7 Hz), 4.01 (q, 2H, J=7 Hz), 3.90 (s,2H), 2.80 (t, 2H, J=7 Hz), 0.94 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 1712,1600, 1498, 1288, 1244. MS (FD⁺) m/e 392. Analytical compositioncalculated for C₂₄H₂₄O₃S C, 73.44; H, 6.16; N, 0. Found C, 72.61; H,5.78; N, 0.20.

e) 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid

4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid wasprepared as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid.4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester (1.6 g, 4.08 mmol, 1 eq.) in 30% aqueous THF was treated withlithium hydroxide (0.29 g, 12.24 mmol, 3 eq.). When complete, thereaction was worked up as described and the resulting oil purified viasilica gel flash chromatography using 50% EtOAc in hexane as the mobilephase.

Fractions containing the product were pooled and the solvent removed invacuo leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylicacid (1.44 g, 97% yield) as an orange oil.

¹H NMR (DMSO-d6) δ 12.68 (s, 1H), 7.71 (m, 1H), 7.56 (m, 1H), 7.42 (m,4H), 7.29 (m, 4H), 6.93 (m, 3H), 4.12 (t, 2H, J=7 Hz), 3.90 (s, 2H),2.82 (t, 2H, J=7 Hz). IR (CHCl₃, cm⁻¹) 1701, 1600, 1498, 1484, 1290,1244. MS (ES⁺) m/e 382 [M+NH₄]⁺. MS (ES⁺) m/e 363.

Example 7 Preparation of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate

Prepared in the same manner as described for example 1. A solution of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.70 g,1.92 mmol, 1 eq.) in anhydrous THF was treated with1,1′-carbonyldiimidazole (0.32 g, 1.96 mmol, 1.02 eq.) and warmed asdescribed. The reaction was allowed to cool and then treated withN,N-dimethylethylenediamine (0.20 g, 2.35 mmol, 1.2 eq.). The reactionwas treated as described in example 1 to give a yellow oil. The oil waspurified by silica gel flash chromatography using 5% 2M NH₃ in methanolin chloroform as the mobile phase. Fractions containing the product werepooled and the solvent removed in vacuo leaving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide (0.50 g, 60% yield) as a bright yellowoil.

The free base was converted to the oxalate salt by adding 0.11 g (1.1eq.) of oxalic acid to an EtOAc/Et₂O solution of the amine. Afterstirring for 1.5 hours,4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate (0.3396 g) was obtained byfiltration as a white solid.

¹H NMR (DMSO-d6) δ 8.37 (t, 1H, J=5 Hz), 7.44 (m, 10H), 6.94 (m, 3H),4.13 (t, 2H, J=7 Hz), 3.90 (s, 2H), 3.37 (m, 2H), 2.93 (t, 2H, J=7 Hz),2.83 (t, 2H, J=7 Hz), 2.65 (s, 6H). IR (KBr,cm⁻¹)3382, 1730, 1648, 1599,1585, 1513, 1498, 1463, 1237, 1172, 1032, 1015, 752, 695. MS (ES⁺) m/e435. MS (ES⁻) m/e 493 [M+OAc]−, 433. Analytical composition calculatedfor C₂₈H₃₂N₂O₆S C, 64.10; H, 6.15; N, 5.34. Found C, 63.08; H, 5.52; N,5.03. Analytical HPLC 96.9% purity. MP 109-113° C.

Example 8 Preparation of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide

Prepared in the same manner as described for example 1. A solution of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.38 g,1.04 mmol, 1 eq.) in anhydrous THF was treated with1,1′-carbonyldiimidazole (0.17 g, 1.06 mmol, 1.02 eq.) and warmed asdescribed. The reaction was allowed to cool and then treated with3-(dimethylamino)propylamine (0.13 g, 1.25 mmol, 1.2 eq.). The reactionwas treated as described in example 1 to give a yellow oil. The oil waspurified by silica gel flash chromatography using 10% 2M NH₃ in methanolin diethyl ether as the mobile phase. Fractions containing the productwere pooled and the solvent removed in vacuo leaving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide (0.40 g, 85% yield) as a light yellowoil.

¹H NMR (DMSO-d6) δ 8.05 (t, 1H, J=5 Hz), 7.38 (m, 10H), 6.93 (m, 3H),4.12 (t, 2H, J=7 Hz), 3.88 (s, 2H), 3.05 (m, 2H), 2.81 (t, 2H, J=7 Hz),2.04 (m, 8H), 1.39 (m, 2H). IR (CHCl₃, cm⁻¹) 3439, 3007, 2949, 2865,2824, 2780, 1649, 1601, 1498, 1243. MS (ES⁺) m/e 449. MS(ES⁻) m/e 447.Analytical composition calculated for C₂₇H₃₂N₂O₂S C, 72.29; H, 7.19; N,6.24. Found C, 71.88; H, 7.27; N, 6.44. Analytical HPLC 100% purity.

Example 9 Preparation of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide oxalate

Prepared in the same manner as described for example 1. A solution of4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.85 g,2.33 mmol, 1 eq.) in anhydrous THF was treated with1,1′-carbonyldiimidazole (0.40 g, 2.45 mmol, 1.05 eq.) and warmed asdescribed. The reaction was allowed to cool and then treated with4-dimethylaminobutylamine (0.33 g, 2.80 mmol, 1.2 eq.). The reaction wastreated as described in example 1 to give a yellow oil. The oil waspurified by silica gel flash chromatography using 5% 2M NH₃ in methanolin chloroform as the mobile phase. Fractions containing the product werepooled and the solvent removed in vacuo leaving4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide (1.06 g, 98% yield) as a light yellow oil.

Converted the free base to the oxalate salt as described in example 4 toobtain 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide oxalate (0.8135 g) as a white solid.

¹H NMR (DMSO-d6) δ 8.15 (t, 1H, J=5 Hz), 7.35 (m, 10H), 6.94 (m, 3H),4.13 (t, 2H, J=7 Hz), 3.89 (s, 2H), 3.06 (m, 2H), 2.93 (m, 2H), 2.82 (t,2H, J=7 Hz), 2.69 (s, 6H), 1.47 (m, 2H), 1.31 (m, 2H). IR (KBr, cm⁻¹)3263, 3167, 3141, 3053, 2922, 2854, 2751, 1730, 1635, 1601, 1585, 1496,1230, 711. MS (ES⁺) m/e 463. MS (ES⁻) 521 [M+OAc]⁻, 461. Analyticalcomposition calculated for C₃₀H₃₆N₂O₆S C, 65.20; H, 6.57; N, 5.07.

Found C, 59.90; H, 6.00; N, 7.54. Analytical HPLC 100% purity. MP 72-76°C.

Preparation of 3′-2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylicacid from ethyl 3-bromobenzoate and 3-methylbenzeneboronic acid

a) 3′-Methyl-biphenyl-2-carboxylic acid ethyl ester

This compound was synthesized essentially as described for the synthesisof 4′-methyl-biphenyl-3-carboxylic acid ethyl ester. Ethyl2-bromobenzoate (5.61 g, 24.51 mmol, 1 eq.) and 3-methylbenzeneboronicacid (3.5 g, 25.74 mmol, 1.05 eq.) in anhydrous THF were treated withpalladium(II) acetate (0.55 g, 2.45 mmol, 10 mol %), triphenylphosphine(2.83 g, 10.78 mmol, 4.4×Pd), copper(I) iodide (0.17 g, 0.89 mmol,catalyst), and aqueous 2M sodium carbonate (26.96 mL, 53.92 mmol, 2.2eq.). When complete, the reaction was worked up as described leaving adark orange/brown oil.

The oil was purified by preparative HPLC (Waters LC-2000) using agradient starting with 100% hexane and going to 8% EtOAc in hexane over30 minutes. Fractions containing the product were pooled and the solventremoved in vacuo leaving 3′-methyl-biphenyl-2-carboxylic acid ethylester (4.36 g, 74% yield) as an orange oil.

¹H NMR (DMSO-d6) δ 7.73 (m, 2H), 7.60 (m, 1H), 7.47 (m, 2H), 7.30 (m,1H), 7.18 (m, 1H), 7.07 (m, 1H), 4.32 and 4.03 (q, 2H total, J=7 Hz,atropisomerism of ester), 2.34 (s, 3H), 1.32 and 0.95 (t, 3H total, J=7Hz, atropisomerism of ester). IR (CHCl₃, cm⁻¹) 1715, 1292, 1251, 1134.MS (ES⁺) m/e 241, 195 [M−OEt]⁺. Analytical composition calculated forC₁₆H₁₆O₂ C, 79.97; H. 6.71; N, 0. Found C, 69.74; H, 5.74; N, 0.32.

b) 3′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester

3′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester was synthesized asdescribed for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester.3′-Methyl-biphenyl-2-carboxylic acid ethyl ester (4.3 g, 17.89 mmol, 1eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.82g, 21.47 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.15 g, 0.89mmol, 5 mol %). When complete, the reaction was worked up as describedleaving a tan oil.

The oil was purified by silica gel flash column chromatography using astep gradient starting with 100% hexane (2 L) and going to 2.5% EtOAc inhexane (2 L) and then 5% EtOAc in hexane (2 L). Fractions containing theproduct were pooled and the solvent removed in vacuo leaving3′-bromomethyl-biphenyl-2-carboxylic acid ethyl ester (5.49 g, 96%yield) as a light yellow oil.

¹H NMR (DMSO-d6) δ 7.76 (m, 1H), 7.64 (m, 1H), 7.46 (m, 4H), 7.33 (m,1H), 7.24 (m, 1H), 4.75 (s, 2H), 4.32 and 4.03 (q, 2H, J=7 Hz,atropisomerism of ester), 1.32 and 0.91 (t, 3H, J=7 Hz, atropisomerismof ester). IR (CHCl₃, cm⁻¹) 1714, 1600, 1293, 1251, 1135. MS (ES⁺) m/e319, 321; 239 [M−Br]⁺. Analytical composition calculated for C₁₆H₁₅BrO₂C, 60.21; H, 4.74. Found C, 51.93; H, 3.92.

c) 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester

3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester was prepared as described for4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 3′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester (5.4 g,16.92 mmol, 1 eq.). in anhydrous DMF was treated with 2-mercaptoethanol(1.59 g, 20.30 mmol, 1.2 eq.) and potassium carbonate (7.02 g, 50.76mmol, 3 eq.). When complete, the reaction was worked up as describedleaving a light yellow oil.

The oil was purified via silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving3′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester (2.15 g, 40% yield) as a light yellow oil.

¹H NMR (DMSO-d6) δ 7.72 (m, 1H), 7.61 (m, 1H), 7.49 (m, 1H), 7.37 (m,3H), 7.24 (s, 1H), 7.16 (m, 1H), 4.77 (t, 1H, J=5 Hz), 4.03 (q, 2H, J=7Hz), 3.79 (s, 2H), 3.53 (m, 2H), 2.50 (m, 2H), 0.94 (t, 3H, J=7 Hz). IR(CHCl₃, cm⁻¹) 3506, 1712, 1600, 1473, 1288, 1250, 1134, 1094, 1052. MS(ES⁺) m/e 299 [M−OH]⁺; 271 [M−OEt]⁺; 239 [M−SCH₂CH₂OH]⁺. Analyticalcomposition calculated for C₁₈H₂O₃S C, 68.33; H, 6.37. Found C, 68.13;H, 6.29.

d) 3′-(12-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester was prepared as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acidethyl ester (2.1 g, 6.64 mmol, 1 eq.) in anhydrous THF was treated withphenol (0.88 g, 9.30 mmol, 1.4 eq.), triphenylphosphine (2.44 g, 9.30mmol, 1.4 eq.), and diisopropyl azidocarboxylate (1.88 g, 1.83 mL, 9.30mmol, 1.4 eq.). When complete, the reaction was worked up as describedleaving a yellow oil

The oil was purified by silica gel flash chromatography using 5% EtOAcin hexane as the mobile phase. Fractions containing the product werepooled and the solvent removed in vacuo leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester (2.15 g, 82% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 57.72 (m, 1H), 7.60 (m, 1H), 7.48 (m, 1H), 7.38 (m,2H), 7.26 (m, 3H), 7.17 (m, 2H), 6.92 (m, 2H), 6.76 (m, 1H), 4.11 (t,2H, J=7 Hz), 4.02 (q, 2H, J=7 Hz), 3.89 (s, 2H), 2.79 (t,2H, J=7 Hz),0.93 (t, 3H, J=7 Hz). IR (CHCl₃,cm⁻¹) 1714, 1599, 1498, 1291, 1245. MS(FD⁺) m/e 392. Analytical composition calculated for C₂₄H₂₄O₃S C, 73.44;H, 6.16. Found C, 66.49; H, 5.55.

e) 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid wassynthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid.3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester (2.1 g, 5.35 mmol, 1 eq.) in 30% aqueous THF was treated withlithium hydroxide (0.38 g, 16.05 mmol, 3 eq.). When complete, thereaction was worked up as described leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (1.94, 99%yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 12.7 (s, 1H), 7.73 (m, 1H), 7.55 (m, 1H), 7.45 (m,1H), 7.26 (m, 7H), 6.92 (m, 2H), 6.76 (m, 1H), 4.10 (t, 2H, J=7 Hz),3.88 (s, 2H), 2.79 (t, 2H, J=7Hz). IR (CHCl₃, cm⁻¹) 3030, 1702, 1599,1587, 1498, 1470, 1294, 1244, 1173. MS (ES⁺) m/e 271 [M−OPh]⁺. MS (ES⁻)m/e 363. Analytical composition calculated for C₂₂H₂₀O₃S C, 72.50; H,5.53. Found C, 61.78; H, 4.59.

Example 10 Preparation of3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide hydrochloride

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (1.02 g,2.8 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.46 g, 2.86 mmol, 1.02 eq.) andN,N-dimethylethylenediamine (0.30 g, 3.36 mmol, 1.2 eq.) as described.When complete, the reaction was worked up as described leaving a yellowoil.

The oil was purified via silica gel flash chromatography using 5% 2M NH₃in methanol in chloroform as the mobile phase. Fractions containing theproduct were pooled and the solvent removed in vacuo leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide (0.92 g, 75% yield) as a light yellow oil.

The free base was converted to the hydrochloride salt by adding asolution of acetyl chloride (0.18 mL, 1.2 eq.) in EtOH (1 mL) dropwiseto an ether solution of the free base. The resulting white solid (0.69g) was collected by filtration and dried in a vacuum oven.

¹H NMR (DMSO-d6) δ 10.48 (s, 1H), 8.49 (t, 1H, J=5 Hz), 7.55-7.24 (m,10H), 6.93 (m, 3H), 4.11 (t, 2H, J=7 Hz), 3.89 (s, 2H), 3.44 (m, 2H),3.03 (t, 2H, J=7 Hz), 2.82 (t, 2H, J=7 Hz), 2.69 (s, 6H). IR (CHCl₃,cm⁻¹) 3424, 3247, 2975, 1658, 1600, 1521, 1498, 1471, 1243. MS (ES⁺) m/e435. MS (ES⁻) m/e 433. Analytical composition calculated forC₂₆H₃₁ClN₂O₂S C, 66.29; H, 6.63; N, 5.95. Found C, 65.94; H, 6.90; N,5.79. MP 150-153° C.

Example 11 Preparation of3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.95 g,2.61 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.43 g, 2.66 mmol, 1.02 eq.) and3-(dimethylamino)propylamine (0.32 g, 3.13 mmol, 1.2 eq.) as described.When complete, the reaction was worked up as described leaving a yellowoil.

The oil was purified via silica gel flash chromatography using 10% 2MNH₃ in methanol in diethyl ether as the mobile phase. Fractionscontaining the product were pooled and the solvent removed in vacuoleaving 3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide (0.42 g, 36% yield) as a light yellowoil.

¹H NMR (DMSO-d6) δ 8.09 (t, 1H, J=5 Hz), 7.46 (m, 1H), 7.41-7.23 (m,9H), 6.92 (m, 3H), 4.10 (t, 2H, J=7 Hz), 3.87 (s, 2H), 3.06 (t, 2H, J=7Hz), 2.80 (t, 2H, J=7 Hz), 2.04 (m, 8H), 1.41 (m, 2H). IR (CHCl₃, cm⁻¹)3439, 3004, 2949, 2865, 2824, 2780, 1649, 1600, 1520, 1497, 1470, 1244,1033. MS (ES⁺) m/e 449. MS (ES⁻) m/e 447. Analytical compositioncalculated for C₂₇H₃₂N₂O₂S C, 72.29; H, 7.19; N, 6.24. Found C, 72.13;H, 7.25; N, 6.25.

Example 12 Preparation of3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.95 g,2.61 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.43 g, 2.66 mmol, 1.02 eq.) and4-dimethylaminobutylamine (0.36 g, 3.13 mmol, 1.2 eq.) as described.When complete, the reaction was worked up as described leaving a yellowoil.

Purified the oil via silica gel flash chromatography using 10% 2M NH₃ inmethanol in diethyl ether as the mobile phase. Fractions containing theproduct were pooled and the solvent removed in vacuo leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide (0.40 g, 33% yield) as a light yellow oil.

¹H NMR (DMSO-d6) δ 8.15 (t, 1H, J=5 Hz), 7.46 (m, 1H), 7.41-7.23 (m,9H), 6.92 (m, 3H), 4.09 (t, 2H, J=7 Hz), 3.87 (s, 2H), 3.05 (m, 2H),2.80 (t, 2H, J=7 Hz), 2.09 (m, 2H), 2.05 (s, 6H), 1.28 (m, 4H). IR(CHCl₃, cm⁻¹) 2944, 2864, 2824, 1650, 1601, 1497, 1221, 1219, 1211. MS(ES⁺) m/e 463. MS (ES⁻) m/e 461. Analytical composition calculated forC₂₈H₃₄N₂O₂S C, 72.69; H, 7.41; N, 6.05. Found C, 68.07; N, 6.91; N,5.74. Analytical HPLC 95% pure.

Preparation of 3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylicacid from 3-methylbenzeneboronic acid and ethyl 3-bromobenzoate

a) 3′-Methyl-biphenyl-3-carboxylic acid ethyl ester

3′-Methyl-biphenyl-3-carboxylic acid ethyl ester was synthesized asdescribed for 4′-methyl-biphenyl-3-carboxylic acid ethyl ester. Ethyl3-bromobenzoate (3.83 g, 16.72 mmol, 1 eq.) and 3-methylbenzeneboronicacid (2.5 g, 18.39 mmol, 1.1 eq.) in THF were treated with aqueoussodium carbonate (2M solution, 18.4 mL, 36.78 mmol, 2.2 eq.),palladium(II) acetate (0.37 g, 1.67 mmol, 10 mol %), triphenylphosphine(1.93 g, 7.35 mmol, 4.4×Pd), and copper(I) iodide (0.1 g, catalyst).When complete, the reaction was worked up as described leaving a brownoil.

The oil was purified by preparative HPLC (Waters LC-2000) using agradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving3′-methyl-biphenyl-3-carboxylic acid ethyl ester (3.04 g, 76% yield) asa faint yellow oil.

¹H NMR (DMSO-d6) δ 8.17 (m, 1H), 7.94 (m, 2H), 7.62 (t, 1H, J=8 Hz),7.48 (m, 2H), 7.39 (t, 1H, J=8 Hz), 7.23 (d, 1H, J=7 Hz), 4.36 (q, 2H,J=7 Hz), 2.40 (s, 2H), 1.35 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 1715,1369, 1312, 1270, 1254, 1111. MS (ES⁺) m/e 241. Analytical compositioncalculated for C₁₆H₁₆O₂ C, 79.97; H, 6.71; N, 0. Found C, 79.65; H,6.75; N, 0.16.

d) 3′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester

3′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester was synthesized asdescribed for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester.3′-Methyl-biphenyl-3-carboxylic acid ethyl ester (4.2 g, 17.48 mmol, 1eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.73g, 20.98 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.14 g, 0.87mmol, 5 mol %). When complete, the reaction was worked up as describedleaving an orange oil.

The oil was purified via silica gel flash chromatography using 5% EtOAcin hexane as the mobile phase. Fractions containing the product werepooled and the solvent removed in vacuo leaving3′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester (4.5 g, 81% yield)as a light yellow oil.

¹H NMR (DMSO-d6) δ 8.06 (m, 1H), 7.95 (m, 1H), 7.86 (m, 1H), 7.64 (m,2H), 7.50 (m, 3H), 4.82 (s, 2H), 4.33 (q, 2H, J=7 Hz), 1.33 (t, 3H, J=7Hz). IR (CHCl₃, cm⁻¹) 1716, 1369, 1296, 1297, 1256, 1111. MS (ES⁺) m/e319, 321. Analytical composition calculated for C₁₆H₁₅BrO₂ C, 60.21; H,4.74. Found C, 53.31; H, 3.29.

c) 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester

3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester was synthesized as described for4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 3′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester (3.4 g,10.65 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol(1.0g, 12.78 mmol, 1.2 eq.) and potassium carbonate (4.42 g, 31.95 mmol,3 eq.). When complete, the reaction was worked up as described leaving ayellow oil.

The oil was purified by silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving3′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester (1.1 g, 33% yield) as a light yellow oil.

¹H NMR (DMSO-d6) δ 8.19 (m, 1H), 7.96 (m, 2H), 7.61 (m, 3H), 7.46 (m,1H), 7.37 (m, 1H), 4.79 (t, 1H, J=5 Hz), 4.36 (q, 2H, J=7 Hz), 3.86 (s,2H), 3.54 (m, 2H), 2.53 (m, 2H1), 1.35 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹)3599, 3507, 3007, 1712, 1254. MS (ES⁺) m/e 299 [M−OH]⁺.

d) 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acidethyl ester (1.0 g, 3.16 mmol, 1 eq.) in anhydrous THF was treated withphenol (0.42 g, 4.42 mmol, 1.4 eq.), triphenylphosphine (1.16 g, 4.42mmol, 1.4 eq.), and diisopropyl azidocarboxylate (0.89 g, 4.42 mmol, 1.4eq.). When complete, the reaction was worked up as described leaving ayellow oil.

The oil was purified via silica gel flash chromatography using 5% EtOAcin hexane as the mobile phase. Fractions containing the product werepooled and the solvent removed in vacuo leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester (0.75 g, 60% yield) as a light yellow oil.

¹H NMR (DMSO-d6) δ 8.18 (m, 1H), 7.94 (m, 2H), 7.62 (m, 3H), 7.44 (m,2H), 7.25 (m, 2H), 6.91 (m, 3H), 4.35 (q, 2H, J=7 Hz), 4.11 (t, 2H, J=7Hz), 3.95 (s, 2H), 2.80 (t, 2H, J=7 Hz), 1.34 (t, 3H, J=7 Hz). MS (FD⁺)m/e 392.

e) 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid wassynthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid.3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester (0.80 g, 2.04 mmol, 1 eq.) in 30% aqueous THF was treated withlithium hydroxide (0.15 g, 6.12 mmol, 3 eq.). When complete, thereaction was worked up as described leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (0.73 g,98% yield) as an orange oil that solidified on standing.

¹H NMR (DMSO-d6) δ 13.1 (s, 1H), 8.19 (m, 1H), 7.92 (m, 2H), 7.69 (s,1H), 7.60 (m, 2H), 7.43 (m, 2H), 7.25 (m, 2H), 6.91 (m, 3H), 4.11 (t,2H, J=7 Hz), 3.95 (s, 2H), 2.80 (t, 2H, J=7 Hz). IR (KBr, cm⁻¹) 1695,1601, 1498,1314, 1241, 757, 748, 691. MS (ES⁺) m/e 382 [M+NH₄]⁺. MS(ES⁻) m/e 363.

Example 13 Preparation of3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide oxalate

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (0.7 g,1.92 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.32 g, 1.96 mmol, 1.02 eq.), and3-(dimethylamino)propylamine (0.30 g, 2.30 mmol, 1.2 eq.) as described.When complete, the reaction was worked up as described leaving a yellowoil.

Purified the oil via silica gel flash chromatography using 10% 2M NH₃ inmethanol in chloroform as the mobile phase. Fractions containing theproduct were pooled and the solvent removed in vacuo leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide (0.65 g, 76% yield) as a faint yellowoil. The free base was converted to the oxalate salt by adding oxalicacid (0.14 g, 1.1 eq) in EtOAc dropwise to a solution of the free basein EtOAc. The resulting gum was dissolved in a little methanol and thesolution added dropwise to vigorously stirred diethyl ether. Theresulting off-white solid was collected by filtration and dried to give3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide oxalate (0.5232 g).

¹H NMR (DMSO-d6) δ 8.77 (t, 1H, J=5 Hz), 8.13 (s, 1H1), 7.82 (m, 2H),7.70 (s, 1H), 7.58 (m, 2H), 7.43 (m, 2H), 7.26 (m, 2H), 6.92 (m, 3H),4.12 (t, 2H, J=7 Hz), 3.95 (s, 2H), 3.35 (m, 2H), 3.04 (m, 2H), 2.81 (t,2H, J=7 Hz), 2.72 (s, 6H), 1.90 (m, 2H). IR (KBr, cm⁻¹) 3413, 3260,3027, 1717, 1636, 1600, 1241, 691, 434. MS (ES⁺) m/e 449. MS (ES⁻) m/e507 [M+OAc]⁻. Analytical composition calculated for C₂₉H₃₄N₂O₆S C,64.66; H, 6.36; N, 5.20. Found C, 63.49; H, 6.50; N, 5.50. AnalyticalHPLC 91.5% purity. MP51-53° C.

Preparation of 3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylicacid from ethyl 4-iodobenzoate and 3-methylbenzeneboronic acid

a) 3′-Methyl-biphenyl4-carboxylic acid ethyl ester

3′-Methyl-biphenyl-4-carboxylic acid ethyl ester was synthesized asdescribed for 4′-methyl-biphenyl-3-carboxylic acid ethyl ester. Ethyl4-iodobenzoate (4.62 g, 16.72 mmol, 1 eq.) and 3-methylbenzeneboronicacid (2.50 g, 18.39 mmol, 1.1 eq.) in THF and aqueous 2M sodiumcarbonate (18.4 mL, 2.2 eq.) were treated with palladium(II) acetate(0.37 g, 1.67 mmol, 10 mol %), triphenylphosphine (1.93 g, 7.35 mmol,4.4×Pd), and copper(I) iodide (0.10 g). When complete, the reaction wasworked up as described leaving a brown oil.

The oil was purified by preparative HPLC (Waters LC2000) using agradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving3′-methyl-biphenyl-4-carboxylic acid ethyl ester (3.91 g, 97% yield) asa yellow oil.

¹H NMR (DMSO-d6) δ 8.03 (d, 2H, J=8 Hz), 7.80 (d, 2H, J=8 Hz), 7.53 (m,2H), 7.39 (t, 1H, J=8 Hz), 7.24 (m, 1H), 4.34 (q, 2H, J=7 Hz), 2.39 (s,3H), 1.34 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 1709, 1609, 1297, 1110. MS(ES⁺) m/e 241. Analytical composition calculated for C₁₆H₁₆O₂ C, 79.97;H, 6.71; N, 0. Found C, 78.84; H, 6.29; N, 0.09.

b) 3′-Bromomethyl-biphenyl4-carboxylic acid ethyl ester

3′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester was synthesized asdescribed for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester.3′-Methyl-biphenyl-4-carboxylic acid ethyl ester (3.80 g, 15.81 mmol, 1eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.1 g,17.39 mmol, 1.1 eq.) and 2,2′-azobisisobutyronitrile (0.13 g, 0.79 mmol,5 mol %). When complete, the reaction was worked up as described leaving3′-bromomethyl-biphenyl-4-carboxylic acid ethyl ester (4.83 g, 96%) as ayellow oil that crystallized on standing.

¹H NMR (DMSO-d6) δ 8.06 (m, 2H), 7.83 (m, 3H), 7.70 (m, 1H), 7.51 (m,2H), 4.79 (s, 2H), 4.34 (q, 2H, J=7 Hz), 1.35 (t, 3H, J=7 Hz). IR(CHCl₃, cm⁻¹) 1710, 1610, 1589, 1478, 1369, 1309, 1281, 1184, 1106,1018. MS (FD⁺)m/e 320, 318.. Analytical composition calculated forC₁₆H₁₅BrO₂ C, 60.21; H, 4.74; N, 0. Found C, 56.33; H, 4.41; N, 0.16.

c) 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester

3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester was synthesized as described for4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 3′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester (4.98 g,15.6 mmol, 1 eq) in anhydrous DMF was treated with 2-mercaptoethanol(2.44 g, 31.20 mmol, 2 eq.) and potassium carbonate (6.47 g, 46.80 mmol,3 eq.). When complete, the reaction was worked up as described leaving ayellow oil.

The oil was purified by silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving3′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester (2.11 g, 43% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 8.04 (d, 2H, J=8 Hz), 7.82 (d, 2H, J=8 Hz), 7.69 (m,1H) 7.61 (m, 1H), 7.43 (m, 2H), 4.77 (t, 1H, J=5 Hz), 4.34 (q, 2H, J=7Hz), 3.84 (s, 2H), 3.52 (m, 2H), 2.50 (m, 2H), 1.34 (t, 3H, J=7 Hz). IR(CHCl₃, cm⁻¹) 3599, 3497, 1709, 1609, 1281, 1109, 1018. MS (FD⁺) m/e316. Analytical composition calculated for C₁₈H₂₀O₃S C, 68.33; H, 6.37;N, 0. Found C, 67.90; H, 6.30; N, 0.27.

d) 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acidethyl ester (1.95 g, 6.16 mmol, 1 eq.) in anhydrous THF was treated withphenol (0.75 g, 8.01 mmol, 1.3 eq.), triphenylphosphine (2.10 g, 8.01mmol, 1.3 eq.), and diisopropyl azidocarboxylate (1.62 g, 8.01 mmol, 1.3eq.). When complete, the reaction was worked up as described leaving anorange oil.

The oil was purified by silica gel flash chromatography using EtOAc inhexane as the mobile phase. Fractions containing the product were pooledand the solvent removed in vacuo leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4carboxylic acid ethyl ester(2.05 g, 85% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 8.03 (d, 2H, J=8 Hz), 7.79 (d, 2H, J=8 Hz), 7.71 (s,1H), 7.62 (m, 1H), 7.44 (m, 2H), 7.26 (m, 2H), 6.92 (m, 3H), 4.34 (q,2H, J=7 Hz), 4.12 (t, 2H, J=7 Hz), 3.94 (s, 2H), 2.81 (t, 2H, J=7 Hz),1.34 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 1933, 1710, 1601, 1498, 1281,1244, 1108, 1018. MS (FD⁺)m/e 392. Analytical composition calculated forC₂₄H₂₄O₃S C, 73.44; H, 6.16; N, 0. Found C, 67.16; H, 5.72; N, 0.10.

e) 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid wassynthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid.3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester (2.0 g, 5.1 mmol, 1 eq.) in 30% aqueous THF was treated withlithium hydroxide (0.37 g, 15.3 mmol, 3 eq.). When complete, thereaction was worked up as described leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (1.68 g,90% yield) as a white solid.

¹H NMR (DMSO-d6) δ 12.96 (s, 1H), 8.01 (d, 2H, J-8 Hz), 7.77 (d, 2H, J=8Hz), 7.71 (s, 1H), 7.62 (m, 1H), 7.44 (m, 2H), 7.26 (m, 2H), 6.92 (m,3H), 4.12.(t, 2H, J=7 Hz), 3.94 (s, 2H), 2.80 (t, 2H, J=7 Hz). IR (KBr,cm⁻¹) 1689, 1607, 1422, 1286, 1243, 1170, 759. MS (ES⁻) m/e 363.Analytical composition calculated for C₂₂H₂₀O₃S C, 72.50; H, 5.53; N, 0.Found C, 72.04; H, 5.55; N, 0.15.

Example 14 Preparation of3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide was synthesized as described for4¹-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g,2.19 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) andN,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq.). When complete,the reaction was worked up as described leaving a yellow oil that latersolidified.

The solid was purified via silica gel flash chromatography using 5% 2MNH₃ in methanol in chloroform as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide (0.32 g, 34% yield) as a yellow oil whichcrystallized.

¹H NMR (DMSO-d6) δ 8.43 (t, 1H, J=5 Hz), 7.92 (d, 2H, J=8 Hz), 7.73 (d,2H, J=8 Hz), 7.70 (m, 1H), 7.61 (m, 1H), 7.42 (m, 2H), 7.26 (m, 2H),6.92 (m, 3H), 4.12 (t, 2H, J-7 Hz), 3.94 (s, 2H), 3.37 (m, 2H), 2.80 (t,2H, J=7 Hz), 2.41 (t, 2H, J=7 Hz), 2.19 (s, 6H). IR (KBr, cm⁻¹) 3302,2762, 1635, 1540, 1501, 1249,1037,750. MS (ES⁺) m/e 435. Analyticalcomposition calculated for C₂₆H₃₀N₂O₂S C, 71.86; H. 6.96; N, 6.45. FoundC, 70.44; H, 6.91; N, 6.22. Analytical HPLC 99% purity. MP 75-78° C.

Example 15 Preparation of3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid(3-dimethylamino-propyl)-amide oxalate

3′-(2-Phenoxy-ethylsulfanylmethyl)-bipheny-4-carboxylic acid(3-dimethylamino-propyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4carboxylic acid (0.80 g,2.19 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) and3-(dimethylamino)propylamine (0.27 g, 2.63 mmol, 1.2 eq.). Whencomplete, the reaction was worked up as described leaving a yellow oil.

Purified the oil via silica gel flash chromatography using 10% 2M NH₃ inmethanol in chloroform as the mobile phase. Fractions containing theproduct were pooled and the solvent removed in vacuo leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(3-dimethylamino-propyl)-amide (0.87 g, 89% yield) as a faint yellowoil.

The free base was converted to the oxalate salt by adding oxalic acid(1.3 eq, 0.21 g) in EtOAc dropwise to an EtOAc solution of the amine.The resulting solution was treated with diethyl ether and cooled. Theresulting white solid was collected by filtration and dried leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(3-dimethylamino-propyl)-amide oxalate (0.5950 g) as a white solid.

¹H NMR (DMSO-d6) δ 8.67 (t, 1H, J=5 Hz), 7.95 (d, 2H, J=8 Hz), 7.75 (d,2H, J=7 Hz), 7.70 (m, 1H), 7.61 (m, 1H), 7.43 (m, 2H), 7.26 (m, 2H),6.92 (m, 3H), 4.12 (t, 2H, J=7 Hz), 3.94 (s, 2H), 3.34 (m, 2H), 3.05 (m,2H), 2.81 (t, 2H, J=7 Hz), 2.74 (s, 6H), 1.89 (m, 2H). IR (KBr, cm⁻¹)3347, 3038, 2940, 1722, 1660, 1644, 1600, 1548, 1490, 1240, 694. MS(ES⁺) m/e 449. Analytical composition calculated for C₂₉H₃₄N₂O₆S C,64.66; H, 6.36; N, 5.20. Found C, 64.03; H, 6.36; N, 5.22. AnalyticalHPLC 100% purity. MP 133-137° C.

Example 16 Preparation of3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid(4-dimethylamino-butyl)-amide oxalate

3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(4-dimethylamino-butyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (1.50 g,4.12 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.68 g, 4.20 mmol, 1.02 eq.) and4-dimethylaminobutylamine (0.57 g, 4.94 mmol, 1.2 eq.). When complete,the reaction was worked up as described leaving a yellow oil.

The oil was purified via silica gel flash chromatography using 5% NH₃ inmethanol in chloroform as the mobile phase. Fractions containing theproduct were pooled and the solvent removed in vacuo leaving3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(4-dimethylamino-butyl)-amide (1.45 g, 76% yield) as a light yellow oil.

The free base was converted to the oxalate salt by adding oxalic acid(0.30 g, 1.05 eq) in EtOAc dropwise to an EtOAc solution of the amine.The resulting white solid was collected by filtration and dried in thevacuum oven.

¹H NMR (DMSO-d6) δ 8.59 (t, 1H, J=8 Hz), 7.95 (m, 2H), 7.73 (m, 2H),7.60 (m, 1H), 7.43 (m, 2H), 7.26 (m, 2H), 7.17 (s, 1H), 6.92 (m, 3H),4.12 (t, 2H, J=7 Hz), 3.94 (s, 2H), 3.30 (m, 2H), 3.04 (m, 2H), 2.81 (t,2H, J=7 Hz), 2.73 (s, 6H), 1.60 (m, 4H). IR (m, 4H). IR (CHCl₃, cm⁻¹)3441, 3293, 1611, 1602, 1586, 1498, 1231. MS (ES⁺) m/e 463. MS (ES⁻) m/e521 [M+OAc]⁻, 461. Analytical composition calculated for C₃₀H₃₆N₂O₆S C,65.20; H, 6.57; N, 5.07. Found C, 62.38; H, 6.41; N, 7.86. AnalyticalHPLC 94.7% purity. MP 85-89° C.

Preparation of 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylicacid from ethyl 2-bromobenzoate and o-tolylboronic acid

a) 2′-Methyl-biphenyl-2-carboxylic acid ethyl ester

2′-Methyl-biphenyl-2-carboxylic acid ethyl ester was synthesized asdescribed for 4′-methyl-biphenyl-3-carboxylic acid ethyl ester. Ethyl2-bromobenzoate (9.98 g, 43.57 mmol, 1 eq.) and o-tolylboronic acid(6.22 g, 45.75 mmol, 1.05 eq.) in THF was treated with aqueous 2M sodiumcarbonate (47.9 mL, 95.85 mmol, 2.2 eq.), palladium(II) acetate (0.98 g,4.36 mmol, 10 mol %), triphenylphosphine (5.03 g, 19.18 mmol, 4.4×Pd),and copper(I) iodide (0.27, catalyst). When complete, the reaction wasworked up as described leaving a dark brown oil.

The oil was purified by silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving2′-methyl-biphenyl-2-carboxylic acid ethyl ester (10.45 g, 99% yield) asan orange oil.

¹H NMR (DMSO-d6) δ 7.84 (m, 1H), 7.62 (m, 1H), 7.50 (m, 1H), 7.24 (m,4H), 7.00 (m, 1H), 3.94 (q, 2H, J=7 Hz), 2.01 (s, 3H), 0.86 (t, 3H, J=7Hz). IR (CHCl₃, cm⁻¹) 2984, 1709, 1599, 1477, 1368, 1291, 1254, 1135,1087. MS (EI⁺) m/e 240. Analytical composition calculated for C₁₆H₁₆O₂C, 79.97; H, 6.71; N, 0. Found C, 78.01; H, 6.66; N, 0.09.

b) 2′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester

2′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester was synthesized asdescribed for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester.2′-Methyl-biphenyl-2-carboxylic acid ethyl ester (10.35 g, 43.07 mmol, 1eq.) in carbon tetrachloride was treated with N-bromosuccinimide (9.20g, 51.68 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.35 g, 2.15mmol, 5 mol %). When complete, the reaction was worked up as describedleaving an orange oil.

The oil was purified via silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving2′-bromomethyl-biphenyl-2-carboxylic acid ethyl ester (13.30, 97% yield)as a yellow oil.

¹H NMR (DMSO-d6) δ (complex due to rotational isomerization) 7.93 (m,1H), 7.62 (m, 3H), 7.36 (m, 3H), 7.07 (m, 1H), 4.48 (d, 1H, J=10 Hz),4.23 (d, 1H, J=10 Hz), 3.94 (m, 2H), 0.85 (M, 3H). IR (CHCl₃, cm⁻¹)1711, 1599, 1475, 1443, 1367, 1291, 1255, 1136. MS (EI⁺) m/e 239[M−Br]⁺. Analytical composition calculated for C₁₆H₁₅BrO₂ C, 60.21; H,4.74; N, 0. Found C, 56.99; H, 4.30; N, 0.08.

e) 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester

2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester was synthesized as described for4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 2′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester (13.2 g,41.35 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol(3.88 g, 49.62 mmol, 1.2 eq.) and potassium carbonate (17.14 g, 124.05mmol, 3 eq.). When complete, the reaction was worked up as describedleaving an orange oil.

The oil was purified via silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving2′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester (8.79 g, 67% yield).

¹H NMR (DMSO-d6) δ 7.88 (m, 1H), 7.63 (m, 1H), 7.52 (m, 1H), 7.43 (m,1H), 7.34 (m, 2H), 7.25 (m, 1H), 7.03 (m, 1H), 4.65 (t, 1H, J=5 Hz),3.93 (q, 2H, J=7 Hz), 3.53 (d, 1H, J=13 Hz), 3.40 (d, 1H, J=13 Hz), 3.32(m, 2H), 2.38 (m, 2H), 0.85 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹) 3499,3019, 3012, 2875, 1709, 1598, 1475, 1444, 1368, 1295, 1254, 1136, 1102,1052, 1083, 1006. MS (ES⁺) m/e 317, 334 [M+NH₄]⁺. Analytical compositioncalculated for C₁₈H₂₀O₃S C, 68.33; H, 6.37; N, 0. Found C, 67.42; H,5.85; N, 0.

f) 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acidethyl ester (5.0 g, 15.80 mmol, 1 eq.) in anhydrous THF was treated withphenol (2.08 g, 22.12 mmol, 1.4 eq.), triphenylphosphine (5.80 g, 22.12mmol, 1.4 eq.), and diisopropyl azidocarboxylate (4.47 g, 22.12 mmol,1.4 eq.). When complete, the reaction was worked up as described leavingan orange oil.

The oil was purified via silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester (4.52 g, 73% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 7.87 (m, 1H), 7.51 (m, 2H), 7.29 (m, 4H), 7.16 (m,1H), 7.04 (m, 1H), 6.92 (m, 1H), 6.78 (m, 3H), 3.89 (m, 4H), 3.65 (d,1H, J=13 Hz), 3.52 (d, 1H, J=13 Hz), 2.67 (m, 2H), 0.85 (t, 3H, J=7 Hz).IR (CHCl₃, cm⁻) 1710, 1600, 1498, 1293, 1244. MS (ES⁺) m/e 393, 410[M+NH]⁺. Analytical composition calculated for C₂₄H₂₄O₃S C, 73.44; H,6.16; N, 0. Found C, 71.91; H, 6.16; N, 0.86.

g) 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid wassynthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethylester (4.4 g, 11.21 mmol, 1 eq.) in 30% aqueous THF/dioxane was treatedwith lithium hydroxide (0.81 g, 33.63 mmol, 3 eq.). When complete, thereaction was worked up as described leaving a brown oil

The oil was purified via silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (3.65 g,89% yield) as a red/brown oil.

¹H NMR (DMSO-d6) δ 12.58 (s, 1H), 7.87 (m, 1H), 7.49 (m, 3H), 7.27 (m,4H), 7.06 (m, 1H), 6.92 (m, 1H), 6.78 (m, 3H), 3.85 (t, 2H, J=7 Hz),3.68 (d, 1H, J=13 Hz), 3.52 (d, 1H, J=13Hz), 2.66 (m, 2H). IR (CHCl₃,cm⁻¹) 3011, 1701, 1600, 1587, 1573, 1498, 1470, 1301, 801. MS (ES⁺) m/e382 [M+NH₄]⁺. MS (ES⁻) m/e 363.

Example 17 Preparation of2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.8 g,2.19 mmol, 1 eq.) in anhydrous THF was treated with1,1′-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) and warmed asdescribed. The reaction was allowed to cool and then treated withN,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq.). The reactionwas treated as described in example 1 to give an orange/brown oil. Theoil was purified by silica gel flash chromatography using 10% 2M NH₃ inmethanol in chloroform as the mobile phase. Fractions containing theproduct were pooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl 2-carboxylic acid(2-dimethylamino-ethyl)-amide (0.81 g, 85% yield) as a faint yellow oil.

The free base was converted to the oxalate salt by adding 0.21 g (1.25eq.) of oxalic acid in EtOAc to an EtOAc/Et₂O solution of the amine.After stirring, 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylicacid (2-dimethylamino-ethyl)-amide oxalate (0.81 g) as a white solid wasobtained by filtration.

¹H NMR (DMSO-d6) δ 8.24 (t, 1H, J=8 Hz), 7.55 (m, 1H), 7.44 (m, 3H),7.28 (m, 4H), 7.10 (m, 1H), 6.93 (m, 1H), 6.81 (m, 3H), 3.88 (t, 2H, J=7Hz), 3.73 (d, 1H, J=13 Hz), 3.58 (d, 1H, J=13 Hz), 3.30 (m, 2H), 2.80(t, 2H, J=7 Hz), 2.69 (m, 2H), 2.60 (s, 6H). IR (KBr, cm⁻¹) 3399, 3278,1703, 1653, 1600, 1586, 1496, 1471, 1302, 1242, 1031, 755. MS (ES⁺) m/e435. MS (ES⁻) m/e 493 [M+OAc]⁻. Analytical composition calculated forC₂₈H₃₂N₂O₆S C, 64.10; H, 6.15; N, 5.34. Found C, 63.20; H, 5.94; N,5.31. Analytical HPLC 98.9% purity. MP 46-50° C.

Example 18 Preparation of2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.7 g,1.92 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.32 g, 1.96 mmol, 1.02 eq.) and3-(dimethylamino)propylamine (0.30 g, 2.30 mmol, 1.2 eq.). Whencomplete, the reaction was worked up as described leaving an orange oil.

The oil was purified via silica gel flash chromatography using 5% NH₃ inmethanol in chloroform as the mobile phase. Fractions containing theproduct were pooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide (0.61 g, 71% yield) as a light yellowoil.

¹H NMR (DMSO-d6) δ 7.72 (t, 1H, J=8 Hz), 7.43 (m, 4H), 7.28 (m, 5H),7.11 (m, 1H), 6.92 (m, 1H), 6.81 (m, 2H), 3.88 (t, 2H, J=7 Hz), 3.75 (d,1H, J=13 Hz), 3.63 (m, 1H, J=13 Hz), 2.96 (m, 2H), 2.69 (m, 2H), 2.01(s, 6H), 1.95 (t, 2H, J=7 Hz), 1.22 (m, 2H). IR (CHCl₃, cm⁻¹) 3423,3311, 1646, 1600, 1497, 1243. MS (ES⁺) m/e 449. MS (ES⁻) m/e 507[M+OAc]⁻, 447. Analytical composition calculated for C₂₇H₃₂N₂O₂S C,72.29; H, 7.19; N, 6.24. Found C, 72.00; H, 7.04; N, 6.16. AnalyticalHPLC 100% purity.

Example 19 Preparation of2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide oxalate

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (1.0 g,2.74 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.45 g, 2.79 mmol, 1.02 eq.) and4-dimethylaminobutylamine (0.35 g, 3.01 mmol, 1.1 eq.). When complete,the reaction was worked up as described leaving a brown oil.

The oil was purified via silica gel flash chromatography using 8% NH₃ inmethanol in chloroform as the mobile phase. Fractions containing theproduct were pooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide (1.23 g, 97% yield) as a faint yellow oil.

The free base was converted to the oxalate salt by adding 0.26 g (1.1eq.) of oxalic acid in EtOAc to an EtOAc solution of the amine. Afterstirring, 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide oxalate (0.91 g) as a white solid wasobtained by filtration.

¹H NMR (DMSO-d6) δ 7.91 (t, 1H, J=8 Hz), 7.43 (m, 4H), 7.28 (m, 5H),7.12 (m, 1H), 6.93 (m, 1H), 6.81 (m, 2H), 3.88 (t, 2H, J=7 Hz), 3.73 (d,1H, J=13 Hz), 3.61 (d, 1H, J=13 Hz), 2.97 (m, 2H), 2.88 (m, 2H), 2.67(m, 8H), 1.38 (m, 2H), 1.16 (m, 2H). IR (KBr, cm⁻¹) 3409, 3167, 3141,2944, 1732, 1703, 1601, 1585, 1404, 1229, 711. MS (ES⁺) m/e 463.Analytical composition calculated for C₃₀H₃₆N₂O₆S C, 65.20; H, 6.57; N;5.07. Found C, 58.89; H, 5.89; N, 7.87. Analytical HPLC 100% purity. MP64-70° C.

Preparation of 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylicacid from ethyl 3-bromobenzoate and o-tolylboronic acid

a) 2′-Methyl-biphenyl-3-carboxylic acid ethyl ester

2′-Methyl-biphenyl-3-carboxylic acid ethyl ester was synthesized asdescribed for 4′-methyl-biphenyl-3-carboxylic acid ethyl ester. Ethyl3-bromobenzoate (8.02 g, 35.03 mmol, 1 eq.) and o-tolylboronic acid (5.0g, 36.78 mmol, 1.05 eq.) in THF were treated with aqueous 2M sodiumcarbonate (38.5 mL, 77.07 mmol, 2.2 eq.), palladium(II) acetate (0.79 g,3.50 mmol, 10 mol %), triphenylphosphine (4.04 g, 15.40 mmol, 4.4×Pd),and copper(I) iodide (0.22 g, catalyst). When complete, the reaction wasworked up as described leaving a dark brown oil.

The oil was purified via silica gel flash chromatography using 5% EtOAcin hexane as the mobile phase. Fractions containing the product werepooled and the solvent removed in vacuo leaving2′-methyl-biphenyl-3-carboxylic acid ethyl ester (8.35 g, 99% yield) asa faint yellow oil.

¹H NMR (DMSO-d6) δ 7.97 (m, 1H), 7.88 (s, 1H), 7.62 (m, 2H), 7.29 (m,4H), 4.33 (q, 2H, J=7 Hz), 2.22 (s, 3H), 1.33 (t, 3H, J=7 Hz). IR(CHCl₃, cm⁻¹) 1714, 1477, 1308, 1284, 1243, 1226, 1109. MS (ES⁺) m/e241. Analytical composition calculated for C₁₆H₁₆O₂ C, 79.97; H, 6.71;N, 0. Found C, 79.35; H, 6.45; N, 0.23.

b) 2′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester

2′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester was synthesized asdescribed for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester.2′-Methyl-biphenyl-3-carboxylic acid ethyl ester (8.3 g, 34.54 mmol, 1eq.) in carbon tetrachloride was treated with N-bromosuccinimide (7.38g, 41.45 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.28 g, 1.73mmol, 5 mol %). When complete, the reaction was worked up as describedleaving an orange oil.

The oil was purified via silica gel flash chromatography using 5% EtOAcin hexane as the mobile phase. Fractions containing the product werepooled and the solvent removed in vacuo leaving2′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester (10.34 g, 94%yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 8.04 (m, 2H), 7.68 (m, 3H), 7.45 (m, 2H), 7.29 (m,1H), 4.57 (s, 2H), 4.34 (q, 2H, J=7 Hz), 1.33 (t, 3H, J=7 Hz). MS (FD⁺)m/e 318, 320.

c) 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester

2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester was synthesized as described for4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 2′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester (10.3 g,32.27 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol(3.03 g, 38.72 mmol, 1.2 eq.) and potassium carbonate (13.38 g, 96.81mmol, 3 eq.). When complete, the reaction was worked up as describedleaving a yellow/orange oil.

The oil was purified via silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving2′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester (8.08 g, 79% yield) as a light yellow oil.

¹H NMR (DMSO-d6) δ 7.99 (m, 2H), 7.70 (m, 1H), 7.61 (m, 1H), 7.41 (m,3H), 7.25 (m, 1H), 4.70 (t, 1H, J=5 Hz), 4.33 (q, 2H, J=7 Hz), 3.68 (s,2H), 3.39 (m, 2H), 2.46 (m, 2H), 1.33 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹)3592, 3518, 1714, 1309, 1296, 1246, 1111. MS (ES⁺) m/e 334 [M+NH₄]⁺, 299[M−OH]⁺. Analytical composition calculated for C₁₈H₂₀O₃S C, 68.33; H,6.37; N, 0. Found C, 68.01; H, 6.09; N, 0.44.

d) 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester

b 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acidethyl ester (4.0 g, 12.64 mmol, 1 eq.) in anhydrous THF was treated withphenol (1.67 g, 17.70 mmol, 1.4 eq.), triphenylphosphine (4.64 g, 17.70mmol, 1.4 eq.), and diisopropyl azidocarboxylate (3.58 g, 17.70 mmol,1.4 eq.). When complete, the reaction was worked up as described leavinga yellow oil.

The oil was purified via silica gel flash chromatography using 10% EtOAcin hexane as the mobile phase. Fractions containing the product werepooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester (3.74 g, 75% yield) as a light yellow oil.

¹H NMR (DMSO-d6) δ 7.96 (m, 2H), 7.69 (m, 1H), 7.54 (m, 2H), 7.38 (m,2H), 7.25 (m, 3H), 6.92 (m, 1H), 6.76 (m, 2H), 4.30 (q, 2H, J=7 Hz),3.92 (t, 2H, J=7 Hz), 3.80 (s, 2H), 2.75 (t, 2H, J=7 Hz), 1.30 (t, 3H,J=7 Hz). IR (CHCl₃, cm⁻¹) 1714, 1600, 1498, 1309, 1297, 1244, 1227,1225. MS (FD⁺) m/e 392. Analytical composition calculated for C₂₄H₂₄O₃SC, 73.44; H, 6.16; N, 0. Found C, 71.34; H. 5.88; N, 0.35.

e) 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid wassynthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester (3.65 g, 9.30 mmol, 1 eq.) in 30% aqueous THF was treated withlithium hydroxide (0.67 g, 27.9 mmol, 3 eq.). When complete, thereaction was worked up as described leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3.39 g,100% yield) as an off-white solid.

¹H NMR (DMSO-d6) δ 13.04 (s, 1H), 7.96 (m, 2H), 7.66 (m, 1H), 7.52 (m,2H), 7.37 (m, 2H), 7.25 (m, 3H), 6.92 (m, 1H), 6.78 (m, 2H), 3.93 (t,2H, J=7 Hz), 3.80 (s, 2H), 2.75 (t, 2H, J=7 Hz). IR (CHCl₃, cm⁻¹) 1695,1601, 1498, 1303, 1244. MS (ES⁺) m/e 382 [M+NH₄]⁺. MS (ES⁻¹) m/e 363.Analytical composition calculated for C₂₂H₂₀O₃S C, 72.51; H, 5.53; N, 0.Found C, 72.55; H, 5.71; N, 0.42.

Example 20 Preparation of2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(2-dimethylamino-ethyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (1.0 g,2.74 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.45 g, 2.79 mmol, 1.02 eq.) followed byN,N-dimethylethylenediamine (0.29 g, 3.29 mmol, 1.2 eq.) as described.When complete, the reaction was worked up as described leaving a yellowoil.

The oil was purified via silica gel flash chromatography using 10% 2MNH₃ in methanol in chloroform as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(2-dimethylamino-ethyl)-amide (1.04 g, 87% yield). The free base wasconverted to the oxalate salt by adding oxalic acid (0.24 g, 1.1 eq.) inEtOAc dropwise to an EtOAc solution of the free base.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate (0.88 g) was collected byfiltration as a white solid.

¹H NMR (DMSO-d6) δ 8.77 (t, 1H, J=8 Hz), 7.88 (m, 2H), 7.61 (m, 1H),7.51 (m, 2H), 7.37 (m, 2H), 7.26 (m, 3H), 6.93 (m, 1H), 6.80 (m, 2H),3.93 (t, 2H, J=7 Hz), 3.82 (s, 2H), 3.59 (m, 2H), 3.16 (t, 2H, J=7 Hz),2.75 (m, 8H). IR (KBr, cm⁻¹) 3362, 1640, 1600, 1545, 1243, 702, 693. MS(ES⁺) m/e 435. MS (ES⁻¹) m/e 493 [M+OAc]⁻¹. Analytical compositioncalculated for C₂₈H₃₂N₂O₆S C, 64.10; H, 6.15; N, 5.34; S, 6.11.

Found C, 63.99; H, 6.12; N, 5.37; S, 6.17. Analytical HPLC 98.3% purity.MP 96-100° C.

Example 21 Preparation of2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide oxalate

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (1.0 g,2.74 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.45 g, 2.79 mmol, 1.02 eq.) followed by3-(dimethylamino)propylamine (0.34 g, 3.29 mmol, 1.2 eq.) as described.When complete, the reaction was worked up leaving a yellow oil. The oilwas purified via silica gel flash chromatography using 10% 2M NH₃ inmethanol in chloroform as the mobile phase. Fractions containing theproduct were pooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide (1.06 g, 86% yield). The free base wasconverted to the oxalate salt by adding oxalic acid (0.26 g, 1.2 eq.) inEtOAc dropwise to an EtOAc solution of the free base.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide oxalate (1.08 g) was collected byfiltration as a white solid.

¹H NMR (DMSO-d6) δ 8.67 (t, 1H, J=8 Hz), 7.87 (m, 2H), 7.59 (m, 1H),7.50 (m, 2H), 7.38 (m, 2H), 7.26 (m, 3H), 6.93 (m, 1H), 6.80 (m, 2H),3.93 (t, 2H, J=7 Hz), 3.82 (s, 2H), 3.33 (m, 2H), 3.05 (m, 2H), 2.73 (m,8H), 1.87 (m, 2H). IR (KBr, cm³¹ ¹) 3384, 1718, 1645, 1601, 1584, 1535,1497, 1474, 1243, 1231, 1200, 1176, 705. MS (ES⁺) m/e 449. MS (ES⁻) m/e507 [M+OAc]⁻. Analytical composition calculated for C₂₉H₃₄N₂O₆S C,64.66; H, 6.36; N, 5.20; S, 5.95. Found C, 62.39; H, 6.17; N, 6.22; S,6.05. Analytical HPLC 98.8% purity. MP 97-100° C. to a glass then125-128° C.

Example 22 Preparation of2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(4-dimethylamino-butyl)-amide oxalate

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(4-dimethylamino-butyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (0.50 g,1.37 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimiidazole (0.23g, 1.40 mmol, 1.02 eq.) followed by4-dimethylaminobutylamine (0.19 g, 1.64 mmol, 1.2 eq.) as described.When complete, the reaction was worked up leaving a yellow oil. The oilwas purified via silica gel flash chromatography using 10% 2M NH₃ inmethanol in chloroform as the mobile phase. Fractions containing theproduct were pooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(4-dimethylamino-butyl)-amide (0.31 g, 49% yield). The free base wasconverted to the oxalate salt by adding oxalic acid (0.07g, 1. 1 eq.) inEtOAc dropwise to an EtOAc solution of the free base.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(4-dimethylamino-butyl)-amide oxalate (0.28 g) was collected byfiltration as a white solid.

¹H NMR (DMSO-d6) δ 8.59 (t, 1H, 3=8 Hz), 7.86 (m, 2H), 7.57 (m, 1H),7.50 (m, 2H), 7.37 (m, 2H), 7.26 (m, 3H), 6.92 (m, 1H), 6.80 (m, 2H),3.92 (t, 2H, J=7 Hz), 3.82 (s, 2H), 3.28 (m, 2H), 3.02 (m, 2H), 2.72 (m,8H), 1.64 (m, 2H), 1.54 (m, 2H). IR (KBr, cm⁻¹) 3381, 1723, 1638, 1601,1584, 1536, 1231, 702. MS (ES⁺) m/e 463. MS (ES⁻¹) m/e 521 [M+OAc]⁻.Analytical composition calculated for C₃₀H₃₆N₂O₆S C, 65.20; H, 6.57; N,5.07. Found C, 60.00; H, 5.94; N, 7.06. Analytical HPLC 96.8% purity. MP96-104° C.

Preparation of 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylicacid from ethyl 4-iodobenzoate and o-tolylboronic acid

a) 2′-Methyl-biphenyl4-carboxylic acid ethyl ester

2′-Methyl-biphenyl-4-carboxylic acid ethyl ester was synthesized asdescribed for 4′-methyl-biphenyl-3-carboxylic acid ethyl ester. Ethyl4-iodobenzoate (6.09 g, 22.06 mmol, 1 eq.) and o-tolylboronic acid (3.3g, 24.27 mmol, 1.1 eq.) in THF were treated with aqueous 2M sodiumcarbonate (24.27 mL, 48.53 mmol, 2.2 eq.), palladium(II) acetate (0.50g, 2.21 mmol, 10 mol %), triphenylphosphine (2.55 g, 9.72 mmol, 4.4×Pd)and copper(I) iodide (0.15 g, catalyst). When complete, the reaction wasworked up as described leaving a dark orange oil.

The oil was purified via preparative HPLC using a gradient of EtOAc inhexane as the mobile phase. Fractions containing the product were pooledand the solvent removed in vacuo leaving 2′-methyl-biphenyl-4-carboxylicacid ethyl ester (4.82 g, 91% yield) as an orange oil.

¹H NMR (DMSO-d6) δ 8.02 (d, 2H, J=8 Hz), 7.49 (d, 2H, J=8 Hz), 7.29 (m,4H), 4.34 (q, 2H, J=7 Hz), 2.23 (s, 3H), 1.35 (t, 3H, J=7 Hz). IR(CHCl₃, cm⁻¹) 1710 1280, 1112, 1102. MS (FD⁺) m/e 240. Analyticalcomposition calculated for C₁₆H₁₆O₂ C, 79.97; H, 6.71; N, 0. Found C,79.66; H, 6.50; N, 0.32.

b) 2′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester

2′-Bromomethyl-biphenyl4-carboxylic acid ethyl ester was synthesized asdescribed for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester.2′-Methyl-biphenyl-4-carboxylic acid ethyl ester (4.4 g, 18.31 mmol, 1eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.58g, 20.14 mmol, 1.1 eq.), and 2,2′-azobisisobutyronitrile (0.15 g, 0.92mmol, 5 mol %). When complete, the reaction was worked up as describedleaving 2′-bromomethyl-biphenyl-4-carboxylic acid ethyl ester (5.77 g,99% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 8.08 (m, 2H), 7.60 (m, 3H), 7.46 (m, 2H), 7.28 (m,1H), 4.60 (s, 2H), 4.34 (m, 2H), 1.35 (t, 3H, J=7 Hz). IR (CHCl₃, cm⁻¹)2980, 1713, 1613, 1369, 1310, 1279, 1180, 1104, 1007. MS (FD⁺) m/e 318,320.

c) 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid ethylester

2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester was synthesized as described for4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 2′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester (5.77 g,18.1 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol(2.83 g, 36.2 mmol, 2 eq.) and potassium carbonate (7.50 g, 54.3 mmol, 3eq.). When complete, the reaction was worked up as described leaving ayellow oil

The oil was purified via silica gel flash chromatography using a stepgradient of EtOAc in hexane as the mobile phase. Fractions containingthe product were pooled and the solvent removed in vacuo leaving2′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester (4.38 g, 76% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 8.03 (d, 2H, J=8 Hz), 7.56 (d, 2H, J=8 Hz), 7.48 (m,1H), 7.37 (m, 2H), 7.24 (m, 1H), 4.70 (t, 1H, J=5 Hz), 4.34 (q, 2H, J=7Hz), 3.70 (s, 2H), 3.37 (m, 2H), 2.44 (t, 2H, J=7 Hz), 1.35 (t, 3H, J=7Hz). IR (CHCl₃, cm⁻¹) 3599, 3506, 1711, 1611, 1369, 1310, 1279, 1113,1103, 1056, 1007. MS (FD⁺) m/e 316. Analytical composition calculatedfor C₁₈H₂₀O₃S C, 68.33; H, 6.37; N, 0. Found C, 66.50; H, 6.06; N, 0.22.

f) 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid ethylester

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethylester. 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acidethyl ester (4.15 g, 13.12 mmol, 1 eq.) in anhydrous THF was treatedwith phenol (1.61 g, 17.06 mmol, 1.3 eq.), triphenylphosphine (4.47 g,17.06 mmol, 1.3 eq.), and diisopropyl azidocarboxylate (3.45 g, 17.06mmol, 1.3 eq.). When complete, the reaction was worked up as describedleaving a yellow oil.

The oil was purified via silica gel flash chromatography using 10% EtOAcin hexane as the mobile phase. Fractions containing the product werepooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester (4.84 g, 94% yield) as a yellow oil.

¹H NMR (DMSO-d6) δ 7.97 (d, 2H, J=8 Hz), 7.54 (m, 3H), 7.38 (m, 2H),7.24 (m, 3H), 6.92 (m, 1H), 6.76 (m, 2H), 4.32 (q, 2H, J=7 Hz), 3.89 (t,2H, J=7 Hz), 3.83 (s, 2H), 2.72 (t, 2H, J=7 Hz), 1.34 (t, 3H, J=7 Hz).IR (CHCl₃, cm⁻¹) 1711, 1600, 1498, 1279, 1243, 1179, 1104. MS (FD⁺) m/e392. Analytical composition calculated for C₂₄H₂₄O₃S C, 73.44; H, 6.16;N, 0. Found C, 71.27; H, 5.96; N, 1.01.

e) 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid wassynthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethylester (4.75 g, 12.10 mmol, 1 eq.) in 30% aqueous THF was treated withlithium hydroxide (0.87 g, 36.30 mmol, 3 eq.). When complete, thereaction was worked up as described leaving a tan solid.

The solid was purified via silica gel flash chromatography using 60%EtOAc in hexane as the mobile phase. Fractions containing the productwere pooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (3.35 g,76% yield) as an off-white solid.

¹H NMR (DMSO-d6) δ 12.98 (s, 1H), 7.99 (d, 2H, J=8 Hz), 7.52 (m, 3H),7.38 (m, 2H), 7.25 (m, 3H), 6.92 (m, 1H), 6.77 (m, 2H), 3.90 (t, 2H, J=7Hz), 3.83 (s, 2H), 2.73 (t, 2H, J=7 Hz). IR (CHCl₃, cm⁻¹) 1678, 1609,1601, 1498, 1324, 1293, 1245, 749. MS (ES⁻) m/e 363. Analyticalcomposition calculated for C₂₂H₂₀O₃S C, 72.50; H, 5.53; N, 0. Found C,71.86; H, 5.17; N, 0.22.

Example 23 Preparation of2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid(2-dimethylamino-ethyl)-amide

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g,2.19 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) followed byN,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq.) as described.When complete, the reaction was worked up leaving a yellow oil. The oilwas purified via silica gel flash chromatography using 140:10:1(CHCl₃/MeOH/NH₄OH) as the mobile phase. Fractions containing the productwere pooled and the solvent removed in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide (0.95 g, 100% yield) as a yellow oil.Recrystallized from diethyl ether to obtain2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide (0.49 g) as a white solid that wascollected by filtration.

¹H NMR (DMSO-d6) δ8.41 (t, 1H, J=8 Hz), 7.90 (d, 2H, J=8 Hz), 7.50 (m,3H), 7.37 (m, 2H), 7.25 (m, 3H), 6.91 (m, 1H), 6.78 (m, 2H), 3.91 (t,2H, J=7 Hz), 3.83 (s, 2H), 3.38 (m, 2H), 2.73 (t, 2H, J=7 Hz), 2.42 (t,2H, J=7 Hz), 2.19 (s, 6H). IR (CHCl₃, cm⁻¹) 3395, 1651, 1601, 1527,1498, 1481, 1243. MS (ES⁺) m/e 435. MS (ES⁻) m/e 433. Analyticalcomposition calculated for C₂₆H₃₀N₂O₂S C, 71.86; H, 6.96; N, 6.45. FoundC, 71.58; H, 6.90; N, 6.36. Analytical HPLC 97.9% purity. MP 93-96° C.

Example 24 Preparation of2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid(3-dimethylamino-propyl)-amide

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(3-dimethylamino-propyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g,2.19 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.36g, 2.23 mmol, 1.02 eq.) followed by3-(dimethylamino)propylamine (0.27 g, 2.63 mmol, 1.2 eq.) as described.When complete, the reaction was worked up leaving a yellow oil thatlater crystallized. The solid was purified via silica gel flashchromatography using 140:10:1 (CHCl₃/MeOH/NH₄OH) as the mobile phase.Fractions containing the product were pooled and the solvent removedleaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(3-dimethylamino-propyl)-amide (0.72 g, 74% yield) as a white solid.

¹H NMR (DMSO-d6) δ 8.53 (t, 1H, J=8 Hz), 7.89 (d, 2H, J=8 Hz), 7.50 (m,3H), 7.37 (m, 2H), 7.24 (m, 3H), 6.91 (m, 1H), 6.78 (m, 2H), 3.91 (t,2H, J=7 Hz), 3.83 (s, 2H), 3.30 (m, 2H), 2.73 (t, 2H, J=7 Hz), 2.27 (t,2H, J=7 Hz), 2.14 (s, 6H), 1.67 (m, 2H). IR (CHCl₃, cm⁻¹) 3308, 3059,2968, 2763, 1630, 1540, 1499, 1247, 1035, 745. MS (ES⁺) m/e 449. MS(ES⁻¹) m/e 447. Analytical composition calculated for C₂₇H₃₂N₂O₂S C,72.29; H, 7.19; N, 6.24. Found C, 71.41; H, 6.91; N, 6.36. AnalyticalHPLC 97.5% purity. MP 98-100° C.

Example 25 Preparation of2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid(4-dimethylamino-butyl)-amide

2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(4-dimethylamino-butyl)-amide was synthesized as described for4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide.2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g,2.19 mmol, 1 eq.) in anhydrous THF was treated with1,1-carbonyldiimidazole (0.36g, 2.23 mmol, 1.02 eq.) followed by4-dimethylaminobutylamine (0.31 g, 2.63 mmol, 1.2 eq.) as described.When complete, the reaction was worked up leaving a yellow oil thatlater crystallized. The solid was purified via silica gel flashchromatography using 5% 2M NH₃ in methanol in chloroform as the mobilephase. Fractions containing the product were pooled and the solventremoved in vacuo leaving2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(4-dimethylamino-butyl)-amide (0.63 g, 62% yield) as a white solid.

¹H NMR (DMSO-d6) δ 8.51 (t, 1H, J=8 Hz), 7.90 (d, 2H, J=8 Hz), 7.50 (m,3H), 7.37 (m, 2H), 7.25 (m, 3H), 6.91 (m, 1H), 6.78 (m, 2H), 3.91 (t,2H, J=7 Hz), 3.83 (s, 2H), 3.30 (m, 2H), 2.73 (t, 2H, J=7 Hz), 2.22 (t,2H, J=7 Hz), 2.11 (s, 6H), 1.49 (m, 4H). IR (KBr, cm⁻¹) 3315, 3065,2921, 2757, 1638, 1542, 1240, 1034, 754. MS (MS⁺) 463. MS (ES⁻¹) 521[M+OAc]⁻¹. Analytical composition calculated for C₂₈H₃₄N₂O₂S C, 72.69;H, 7.41; N, 6.05. Found C, 72.46; H, 7.49; N, 6.40. Analytical HPLC94.7% purity. MP softening staring at 65° C. then 72-75° C.

1. A compound of formula I:

or a pharmaceutically acceptable salt, solvate, enantiomer, mixture ofdiastereomers, or prodrug thereof; wherein Ar¹ is a cyclic groupoptionally substituted with one to five groups selected from C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, hydroxy, C₁-C₈ alkoxy, C₁-C₈alkylaryl, phenyl, aryl, C₃-C₈ cycloalkyl, C₁-C₈ alkylcycloalkyl, cyano,—(CH₂)_(n)NR¹R², C₁-C₈ haloalkyl, halo, (CH₂)_(n)COR⁶,(CH₂)_(n)NR⁵SO₂R⁶, —(CH₂)_(n)C(O)NR¹R², and C₁-C₈ alkylheterocyclic;wherein the alkyl, alkenyl, cycloalkyl, phenyl, and aryl are eachoptionally substituted with one to three groups selected from hydroxy,C₁-C₈ alkoxyalkyl, C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl, nitro, cyano,amino, carboxamido, and oxo; L¹ is a bond or a linker having a mainchain of 1 to 14 atoms or represented by the formula X₂—(CR³R⁴)_(m)—X₃wherein R³ and R⁴ are independently hydrogen, C₁-C₈ alkyl, C₂-C₈alkylene, C₂-C₈ alkynyl, phenyl, aryl, C₁-C₈ alkylaryl,(CH₂)_(n)NR⁵SO₂R⁶, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR¹R² or(CH₂)_(n)C(O)OR⁶; wherein the alkyl, alkenyl, phenyl, and aryl groupsare optionally substituted with one to five substitutents independentlyselected from oxo, nitro, cyano, C₁-C₈ alkyl, aryl, halo, hydroxy, C₁-C₈alkoxy, C₁-C₈ halaoalkyl, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR¹R² and(CH₂)_(n)C(O)OR⁶; X₂ is independently —O, —CH, —CHR⁶, —NR⁵, S, SO, orSO₂; X₃ is independently —O, —CH, —CHR⁶, —NR⁵, S, SO, or SO₂; Ar² is a6-member monocyclic carbocyclic or heterocyclic group or positionalisomer thereof, having 0, 1, 2, or 3 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur; and optionally substituted with one tothree substitutents selected from C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, hydroxy, C₁-C₈ alkoxy, C₁-C₈ alkylaryl, phenyl, aryl, C₃-C₈cycloalkyl, C₁-C₈ alkylcycloalkyl, cyano, C₁-C₈ haloalkyl, halo,(CH₂)_(n)C(O)R⁶, (CH₂)_(n)C(O)OR⁶, (CH₂)_(n)NR⁵SO₂R⁶,(CH₂)_(n)C(O)NR¹R², and C₁-C₈ alkylheterocyclic; provided that theresult of the substitution is a stable fragment or group; Ar³ is a6-member monocyclic aromatic or nonaromatic, carbocyclic or heterocyclicring having 0, 1, 2, or 3 heteroatoms selected from nitrogen, oxygen andsulfur and optionally substituted with one to three substitutentsindependently selected from halo, —NHR⁵, C₁-C₈ haloalkyl, C₃-C₈cycloalkyl, C₁-C₈ alkyl, hydroxy, alkoxy, (CH₂)_(n)C(O)R⁶,(CH₂)_(n)C(O)OR⁶, (CH₂)_(n)NR⁵SO₂R⁶, (CH₂)_(n)C(O)NR¹R², phenyl, C₁-C₈alkylaryl, and aryl; provided that Ar² and Ar³ or positional isomn erszthereof are linked by a bond; L² is a bond or a divalent linker having achain length of between 1 and 14 atoms in the main chain or representedby the formula: X₄—(CR³R⁴)_(m)—X₅ wherein R³ and R⁴ are independentlyhydrogen, C₁-C₈ alkyl, C₂-C₈ alkylene, C₂-C₈ alkynyl, phenyl, aryl,C₁-C₈ alkylaryl, (CH₂)_(n)NR⁵SO₂R⁶, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR¹R² or(CH₂)_(n)C(O)OR⁶; wherein the alkyl, alkenyl, phenyl, and aryl groupsare optionally substituted with one to five substitutents independentlyselected from oxo, nitro, cyano, C₁-C₈ alkyl, aryl, halo, hydroxy, C₁-C₈alkoxy, C₁-C₈ halaoalkyl, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR¹R² and(CH₂)_(n)C(O)OR⁶; wherein X₄ is selected from the group consisting of—CH, CHR⁶, —O, —NR⁵, —NC(O)—, —NC(S), —C(O)NR⁵—, —NR⁶C(O)NR⁶,—NR⁶C(S)NR⁶, —NRSO₂R⁷, and —NR⁶C(NR⁵) NR⁶; X₅ is selected from the groupconsisting of —CH₂, —CH, —OCH₂CH₂, —SO, —SO₂, —S, and —SCH₂; wherein thegroup X₄—(CR³R⁴)_(m)—X₅ imparts stability to the compound of formula (1)and may be a saturated or unsaturated chain or linker; Q is a basicgroup or a group represented by —NR¹R² ; wherein R¹ and R² areindependently selected from hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₈cycloalkane, C₁-C₈ alkylaryl, —C(O)C₁-C₈ alkyl, —C(O)OC₁-C₈ alkyl, C₁-C₈alkylcycloalkane, (CH₂)_(n)C(O)OR⁵, (CH₂)_(n)C(O)R⁵, (CH₂)_(n)C(O)NR¹R²,and (CH₂)_(n)NSO₂R⁵; wherein each of the alkyl, alkenyl, aryl are eachoptionally substituted with one to five groups independently selectedfrom C₁-C₈ alkyl, C₂-C₈ alkenyl, phenyl, and alkylaryl; and wherein R¹and R² may combine together, and with the nitrogen atom to which theyare attached or with 0, 1, or 2 atoms adjacent to the nitrogen atom toform a nitrogen containing heterocycle which may have substituents; R⁵is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₅-C₈ alkylaryl,(CH₂)_(n)NSO₂C₁-C₈ alkyl, (CH₂)_(n)NSO₂phenyl, (CH₂)_(n)NSO₂aryl,—C(O)C₁-C₈ alkyl, or —C(O)OC₁-C₈ alkyl; and R⁶ is a group independentlyselected from hydrogen, C₁-C₈ alkyl, phenyl, aryl, C₁-C₈ alkylaryl, andC₃-C₈ cycloalkyl; wherein m is an integer from 0 to 4; and n is aninteger from 0 to
 3. 2. A compound according to claim 1 wherein the Ar¹is selected from the group consisting of cycloheptane, cyclohexane,cyclopentane, phenyl, pyrrolidine, pyridine, piperidine, piperazine,2-indolyl, isoindolyl, thiophene, benzo(b)thiophenyl, napthyl,benzofuranyl and benzthiazolyl.
 3. A compound according to claim 1wherein the group L₁ is a linker selected from the group consisting of:—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —SCH₂—, —OCH₂—, —CH₂SCH₂—,—CH₂OCH₂—,—OCH₂CH₂OCH₂—, —OCH₂CH₂SCH₂—, —O(CH₂)₃SCH₂—,—OCH(Et)CH₂CH₂SCH₂, —OCH(iPr)CH₂CH₂SCH₂—,—OCH(CH₃)CH₂CH₂SCH₂,—O(CH₂)₃SCH(CH₃)—, —O(CH₂)₂SCH(CF₃)—,—OCH₂CH(NO₂)SCH₂—, —OCH(CN)CH₂SCH₂, —OCH₂CH₂OCH₂—, —O(CH₂)₃OCH₂—,—OCH(Et)CH₂CH₂OCH₂, —OCH₂CH(NH₂)SCH₂—, —CH₂O(CH₂)₃CH₂O—,—CH₂O(CH₂)₂CH₃O—, and —(CH₂)₄SCH₂—.
 4. A compound according to claim 1wherein Ar² is a 6-member aromatic group selected from the groupconsisting of pyridazinyl, pyrimidinyl, pyran, piperidinyl, phenyl,cyclohexyl, pyridinyl and piperazinyl.
 5. A compound of claim 1 whereinAr³ is a 6-member aromatic group selected from the group consisting of:phenyl, pyran, piperidine, pyridine, pyridazine, and piperazine.
 6. Acompound according to claim 1 wherein the group Ar³ is selected fromphenyl or phenyl substituted with 1 to 3 substituents selected fromchloro, fluoro, trifluoromethyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, phenyl,aryl, C₁-C₈ alkylaryl, (CH₂)_(n)C(O)R⁶, (CH₂)_(n)CONR¹R², and(CH₂)_(n)OR⁶.
 7. A compound according to claim 1 wherein Ar² and Ar³ areboth phenyl each optionally substituted with one to three substituentsindependently selected from chloro, fluoro, trifluoromethyl, C₁-C₈alkyl, C₂-C₈ alkenyl, phenyl, aryl, C₁-C₈ alkylaryl, (CH₂)_(n)C(O)R⁶,(CH₂)_(n)CONR¹R², and (CH₂)_(n) OR⁶.
 8. A compound according to claim 1wherein the linker (L²) is: —OCH₂CH₂—, —O(CH₂)₃—, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH═CHCH₂—, —CH═CHCH₂CH₂—, —C═CCH₂—, —CONHCH₂CH₂CH₂—,—CONHCH₂CH₂—, —NHCONHCH₂CH₂—, —NHCONHCH₂CH₂CH₂—,—NHCSNHCH₂CH₂—,—NHCSNHCH₂CH₂CH₂—, —NHC(CN)NHCH₂CH₂—, —NHC(CN)NHCH₂CH₂CH₂—,—NHCOCH₂CH₂—, and —NHCOCH₂CH₂CH₂—.
 9. A compound according to claim 1wherein the linker L² is: —CONHCH₂CH₂CH₂—, —CONHCH₂CH₂—, or —CONHCH₂CH₂CH₂CH₂—.
 10. A compound according to claim 1 wherein for Q, R¹ and R²combine to form piperidinyl, pyrrolidinyl, azepine, or azetidinyl.
 11. Acompound according to claim 1 wherein R¹ and R² are independentlyselected from the group consisting of hydrogen, methyl, ethyl, propyl,isopropyl, methylcyclopentane, methylcyclohexane, phenyl,2-fluorophenyl, benzyl, and C(O)Me.
 12. A compound according to claim 1wherein at least one of L₁ and L₂ has a chain length of between 3 to 8atoms.
 13. A compound according to claim 1 wherein L₂ has a chain lengthof between 1 to 8 atoms.
 14. A compound selected from the groupconsisting of: 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylicacid (3-dimethylamino-propyl)-amide oxalate

4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate,

4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(4-dimethylamino-butyl)-amide oxalate,

4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate,

4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(3-dimethylamino-propyl)-amide hydrochloride,

4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(4-dimethylamino-butyl)-amide oxalate,

4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate,

4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide,

4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide oxalate,

3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide hydrochloride,

3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide,

3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide,

3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide oxalate,

3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide,

3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(3-dimethylamino-propyl)-amide oxalate,

3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(4-dimethylamino-butyl)-amide oxalate,

2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate,

2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(3-dimethylamino-propyl)-amide

b 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid(4-dimethylamino-butyl)-amide, oxalate,

2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(2-dimethylamino-ethyl)-amide oxalate,

b 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(3-dimethylamino-propyl)-amide oxalate,

2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(4-dimethylamino-butyl)-amide oxalate,

2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(2-dimethylamino-ethyl)-amide,

2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(3-dimethylamino-propyl)-amide,

2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid(4-dimethylamino-butyl)-amide,

and a pharmaceutically acceptable salt, enatiomer, solvate or prodrugthereof.
 15. The compound of claim 1 which is the oxalate salt, thehydrochloride salt, or the bisulfate salt.
 16. A method of treatingobesity comprising administering to a patient in need thereof a compoundof claim
 1. 17. A method of preventing Type II Diabetes comprisingadministering to a patient in need thereof a compound of claim
 1. 18. Amethod of inhibiting release of the melanin concentrating hormonecomprising administering to a patient in need thereof a compound ofclaim
 1. 19. A method of treating, preventing or ameliorating thesymptoms of obesity and related diseases comprising administering to apatient in need thereof, a therapeutically effective amount of acompound of formula I.
 20. A pharmaceutical formulation comprising acompound of claim 1 and a pharmaceutical carrier for the treatment ofobesity and related diseases.
 21. Use of a compound of formula I in themanufacturre of a medicament for the treatment of obesity and relateddiseases including diabetes mellitus, hyperglycemia, obesity,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,atherosclerosis of coronary, cerebrovascular and peripheral arteries,gastrointestinal disorders including peptid ulcer, esophagitis,gastritis and. duodenitis, (including that induced by H. pylori),intestinal ulcerations (including inflammatory bowel disease, ulcerativecolitis, Crohn's disease and proctitis) and gastrointestinalulcerations, neurogenic inflammation of airways, including cough,asthma, depression, prostate diseases such as benign prostatehyperplasia, irritable bowel syndrome and other disorders needingdecreased gut motility, diabetic retinopathy, neuropathic bladderdysfunction, elevated intraocular pressure and glaucoma and non-specificdiarrhea dumping syndrome.